Datasets:

bigbio

/

bionlp_st_2011_ge

like 0

[ { "id": "PMC-2791889-08-Results-07__text", "type": "abstract", "text": [ "c-maf Expression Correlates with IL-10 Production in Th1, Th2, and Th17 Cells\nTo investigate further the downstream factors involved in regulating IL-10 production, we differentiated DO11.10 CD4+ Tcells with increasing doses of OVA, in the presence or absence of IL-12, and quantified the expression of cytokines and transcription factors by real-time RT-PCR. Low-dose antigen resulted in transcription of Il4 and this was abrogated by both high antigen doses and IL-12 (Figure6A). A low amount of transcription of Ifngamma was induced by IL-12 when cells were differentiated with low antigen dose, but this effect of IL-12 was markedly upregulated with increasing doses of antigen (Figure6A). A low amount of Il10 transcription was observed at low doses of antigen accompanying Il4 expression (Th2 cell response), and this was abrogated by increased doses of antigen as was Il4 expression (Figure6A). At low doses of antigen, IL-12 had little effect to increase IL-10 mRNA expression (Figure6A) in keeping with the protein data (Figure1A). However, IL-12 induced a high amount of Il10 transcription as well as Ifngamma expression with increased antigen doses (Figure6A), again in keeping with the protein data (Figure1A). \nCD4+ Tcells differentiated with increasing doses of antigen did not express high amounts of Tbx-21 (T-bet) mRNA, unless they were cocultured with IL-12 (Figure6B). In contrast, high amounts of GATA-3 mRNA expression were only observed under Th2 cell differentiation conditions (low-dose antigen) (Figure6B), and this expression was markedly downregulated by both increasing antigen dose and coculture in IL-12 (Figure6B). Differentiation of Tcells under low antigen dose led to expression of c-maf, in keeping with the Th2 cell profile (Ho etal., 1996), which was almost completely abrogated by increasing doses of antigen (Figure6B). Interestingly, IL-12 sustained the high expression of c-Maf mRNA even at the highest antigen dose (Figure6B). Moreover, IL-12 maintenance of c-maf expression required STAT4 activation (data not shown). \nIn Th17 cells that expressed IL-17a as well as IL-10 mRNA (Figure6C), T-bet and GATA-3 mRNA were undetectable (data not shown), whereas that of ROR-gammat was high (Figure6C) (Ivanov etal., 2007). Th17 cells also expressed high amounts of c-maf (Figure6C), confirming a recent report (Bauquet etal., 2009). c-Maf is therefore expressed in all IL-10-expressing Tcell populations tested (Figures 6B and 6C) and may not be just a Th2 cell-specific transcription factor as originally thought (Ho etal., 1996). We showed also that like Il10 expression, c-maf expression was inhibited in Th1 and Th17 cells in the presence of the MEK1 and MEK2 inhibitor (PD184352), whereas T-bet and RORgammat expression was hardly affected (Figure6D). \n" ], "offsets": [ [ 0, 2794 ] ] } ]

[ { "id": "PMC-2791889-08-Results-07_T1", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T2", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 33, 38 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T3", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 147, 152 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T4", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 191, 194 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T5", "type": "Protein", "text": [ "OVA" ], "offsets": [ [ 228, 231 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T6", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 263, 268 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T7", "type": "Protein", "text": [ "Il4" ], "offsets": [ [ 406, 409 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T8", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 464, 469 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T9", "type": "Protein", "text": [ "Ifngamma" ], "offsets": [ [ 515, 523 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T10", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 539, 544 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T11", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 618, 623 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T12", "type": "Protein", "text": [ "Il10" ], "offsets": [ [ 710, 714 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T13", "type": "Protein", "text": [ "Il4" ], "offsets": [ [ 779, 782 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T14", "type": "Protein", "text": [ "Il4" ], "offsets": [ [ 875, 878 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T15", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 927, 932 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T16", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 963, 968 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T17", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 1050, 1055 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T18", "type": "Protein", "text": [ "Il10" ], "offsets": [ [ 1081, 1085 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T19", "type": "Protein", "text": [ "Ifngamma" ], "offsets": [ [ 1111, 1119 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T20", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1224, 1227 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T21", "type": "Protein", "text": [ "Tbx-21" ], "offsets": [ [ 1316, 1322 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T22", "type": "Protein", "text": [ "T-bet" ], "offsets": [ [ 1324, 1329 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T23", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 1370, 1375 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T24", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 1417, 1423 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T25", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 1628, 1633 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T26", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 1716, 1721 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T27", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 1874, 1879 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T28", "type": "Protein", "text": [ "c-Maf" ], "offsets": [ [ 1913, 1918 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T29", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 1979, 1984 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T30", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 2000, 2005 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T31", "type": "Protein", "text": [ "STAT4" ], "offsets": [ [ 2026, 2031 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T32", "type": "Protein", "text": [ "IL-17a" ], "offsets": [ [ 2091, 2097 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T33", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 2109, 2114 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T34", "type": "Protein", "text": [ "T-bet" ], "offsets": [ [ 2132, 2137 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T35", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 2142, 2148 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T36", "type": "Protein", "text": [ "ROR-gammat" ], "offsets": [ [ 2206, 2216 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T37", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 2301, 2306 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T38", "type": "Protein", "text": [ "c-Maf" ], "offsets": [ [ 2369, 2374 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T39", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 2405, 2410 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T40", "type": "Protein", "text": [ "Il10" ], "offsets": [ [ 2593, 2597 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T41", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 2610, 2615 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T42", "type": "Protein", "text": [ "MEK1" ], "offsets": [ [ 2686, 2690 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T43", "type": "Protein", "text": [ "MEK2" ], "offsets": [ [ 2695, 2699 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T44", "type": "Protein", "text": [ "T-bet" ], "offsets": [ [ 2730, 2735 ] ], "normalized": [] }, { "id": "PMC-2791889-08-Results-07_T45", "type": "Protein", "text": [ "RORgammat" ], "offsets": [ [ 2740, 2749 ] ], "normalized": [] } ]

[ { "id": "PMC-2791889-08-Results-07_E1", "type": "Gene_expression", "trigger": { "text": [ "Expression" ], "offsets": [ [ 6, 16 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T1" } ] }, { "id": "PMC-2791889-08-Results-07_E2", "type": "Gene_expression", "trigger": { "text": [ "Production" ], "offsets": [ [ 39, 49 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T2" } ] }, { "id": "PMC-2791889-08-Results-07_E3", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 136, 146 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E4" } ] }, { "id": "PMC-2791889-08-Results-07_E4", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 153, 163 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T3" } ] }, { "id": "PMC-2791889-08-Results-07_E5", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 377, 385 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E6" } ] }, { "id": "PMC-2791889-08-Results-07_E6", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 389, 402 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T7" } ] }, { "id": "PMC-2791889-08-Results-07_E7", "type": "Negative_regulation", "trigger": { "text": [ "abrogated" ], "offsets": [ [ 423, 432 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E5" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_T8" } ] }, { "id": "PMC-2791889-08-Results-07_E8", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 498, 511 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T9" } ] }, { "id": "PMC-2791889-08-Results-07_E9", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 528, 535 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E8" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_T10" } ] }, { "id": "PMC-2791889-08-Results-07_E10", "type": "Positive_regulation", "trigger": { "text": [ "this effect" ], "offsets": [ [ 603, 614 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E8" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_T11" } ] }, { "id": "PMC-2791889-08-Results-07_E11", "type": "Positive_regulation", "trigger": { "text": [ "upregulated" ], "offsets": [ [ 637, 648 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E10" } ] }, { "id": "PMC-2791889-08-Results-07_E12", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 715, 728 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T12" } ] }, { "id": "PMC-2791889-08-Results-07_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 783, 793 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T13" } ] }, { "id": "PMC-2791889-08-Results-07_E14", "type": "Negative_regulation", "trigger": { "text": [ "abrogated" ], "offsets": [ [ 828, 837 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E12" } ] }, { "id": "PMC-2791889-08-Results-07_E15", "type": "Negative_regulation", "trigger": { "text": [ "abrogated" ], "offsets": [ [ 828, 837 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E16" } ] }, { "id": "PMC-2791889-08-Results-07_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 879, 889 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T14" } ] }, { "id": "PMC-2791889-08-Results-07_E17", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 944, 950 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E18" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_T15" } ] }, { "id": "PMC-2791889-08-Results-07_E18", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 954, 962 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E19" } ] }, { "id": "PMC-2791889-08-Results-07_E19", "type": "Transcription", "trigger": { "text": [ "mRNA expression" ], "offsets": [ [ 969, 984 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T16" } ] }, { "id": "PMC-2791889-08-Results-07_E20", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1056, 1063 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E21" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_T17" } ] }, { "id": "PMC-2791889-08-Results-07_E22", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1056, 1063 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E23" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_T17" } ] }, { "id": "PMC-2791889-08-Results-07_E21", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1086, 1099 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T18" } ] }, { "id": "PMC-2791889-08-Results-07_E23", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1120, 1130 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T19" } ] }, { "id": "PMC-2791889-08-Results-07_E24", "type": "Transcription", "trigger": { "text": [ "express" ], "offsets": [ [ 1292, 1299 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T21" } ] }, { "id": "PMC-2791889-08-Results-07_E25", "type": "Transcription", "trigger": { "text": [ "mRNA expression" ], "offsets": [ [ 1424, 1439 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T24" } ] }, { "id": "PMC-2791889-08-Results-07_E26", "type": "Negative_regulation", "trigger": { "text": [ "downregulated" ], "offsets": [ [ 1565, 1578 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E25" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_T25" } ] }, { "id": "PMC-2791889-08-Results-07_E27", "type": "Positive_regulation", "trigger": { "text": [ "led" ], "offsets": [ [ 1695, 1698 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E28" } ] }, { "id": "PMC-2791889-08-Results-07_E28", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1702, 1712 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T26" } ] }, { "id": "PMC-2791889-08-Results-07_E29", "type": "Negative_regulation", "trigger": { "text": [ "abrogated" ], "offsets": [ [ 1806, 1815 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E28" } ] }, { "id": "PMC-2791889-08-Results-07_E30", "type": "Positive_regulation", "trigger": { "text": [ "sustained" ], "offsets": [ [ 1880, 1889 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E31" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_T27" } ] }, { "id": "PMC-2791889-08-Results-07_E31", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 1899, 1909 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T28" } ] }, { "id": "PMC-2791889-08-Results-07_E32", "type": "Positive_regulation", "trigger": { "text": [ "maintenance" ], "offsets": [ [ 1985, 1996 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E33" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_T29" } ] }, { "id": "PMC-2791889-08-Results-07_E33", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2006, 2016 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T30" } ] }, { "id": "PMC-2791889-08-Results-07_E34", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 2017, 2025 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E35" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_E33" } ] }, { "id": "PMC-2791889-08-Results-07_E35", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 2032, 2042 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T31" } ] }, { "id": "PMC-2791889-08-Results-07_E36", "type": "Transcription", "trigger": { "text": [ "expressed" ], "offsets": [ [ 2081, 2090 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T32" } ] }, { "id": "PMC-2791889-08-Results-07_E37", "type": "Transcription", "trigger": { "text": [ "expressed" ], "offsets": [ [ 2081, 2090 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T33" } ] }, { "id": "PMC-2791889-08-Results-07_E38", "type": "Transcription", "trigger": { "text": [ "mRNA" ], "offsets": [ [ 2149, 2153 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T34" } ] }, { "id": "PMC-2791889-08-Results-07_E39", "type": "Transcription", "trigger": { "text": [ "mRNA" ], "offsets": [ [ 2149, 2153 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T35" } ] }, { "id": "PMC-2791889-08-Results-07_E40", "type": "Negative_regulation", "trigger": { "text": [ "undetectable" ], "offsets": [ [ 2159, 2171 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E38" } ] }, { "id": "PMC-2791889-08-Results-07_E41", "type": "Negative_regulation", "trigger": { "text": [ "undetectable" ], "offsets": [ [ 2159, 2171 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E39" } ] }, { "id": "PMC-2791889-08-Results-07_E42", "type": "Positive_regulation", "trigger": { "text": [ "high" ], "offsets": [ [ 2221, 2225 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T36" } ] }, { "id": "PMC-2791889-08-Results-07_E43", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 2275, 2284 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T37" } ] }, { "id": "PMC-2791889-08-Results-07_E44", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 2388, 2397 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T38" } ] }, { "id": "PMC-2791889-08-Results-07_E45", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 2411, 2421 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T39" } ] }, { "id": "PMC-2791889-08-Results-07_E46", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2598, 2608 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T40" } ] }, { "id": "PMC-2791889-08-Results-07_E47", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2616, 2626 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T41" } ] }, { "id": "PMC-2791889-08-Results-07_E48", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 2631, 2640 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E46" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_E49" } ] }, { "id": "PMC-2791889-08-Results-07_E50", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 2631, 2640 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E46" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_E51" } ] }, { "id": "PMC-2791889-08-Results-07_E52", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 2631, 2640 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E47" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_E49" } ] }, { "id": "PMC-2791889-08-Results-07_E53", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 2631, 2640 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E47" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_E51" } ] }, { "id": "PMC-2791889-08-Results-07_E49", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 2700, 2709 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T42" } ] }, { "id": "PMC-2791889-08-Results-07_E51", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 2700, 2709 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T43" } ] }, { "id": "PMC-2791889-08-Results-07_E54", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2750, 2760 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T44" } ] }, { "id": "PMC-2791889-08-Results-07_E55", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2750, 2760 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_T45" } ] }, { "id": "PMC-2791889-08-Results-07_E56", "type": "Regulation", "trigger": { "text": [ "affected" ], "offsets": [ [ 2772, 2780 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E54" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_E49" } ] }, { "id": "PMC-2791889-08-Results-07_E57", "type": "Regulation", "trigger": { "text": [ "affected" ], "offsets": [ [ 2772, 2780 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E54" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_E51" } ] }, { "id": "PMC-2791889-08-Results-07_E58", "type": "Regulation", "trigger": { "text": [ "affected" ], "offsets": [ [ 2772, 2780 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E55" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_E49" } ] }, { "id": "PMC-2791889-08-Results-07_E59", "type": "Regulation", "trigger": { "text": [ "affected" ], "offsets": [ [ 2772, 2780 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-08-Results-07_E55" }, { "role": "Cause", "ref_id": "PMC-2791889-08-Results-07_E51" } ] } ]

[ { "id": "PMC-2791889-08-Results-07_1", "entity_ids": [ "PMC-2791889-08-Results-07_T21", "PMC-2791889-08-Results-07_T22" ] } ]

[]

[ { "id": "PMC-2791889-09-Discussion__text", "type": "abstract", "text": [ "Discussion\nIL-10 expression by cells of the innate and adaptive immune systems reflects the importance of this cytokine in the tight regulation of the immune response, to minimize pathology during infection. IL-10 expression by Th1 cells has been reported to regulate the immune response in leishmaniasis and toxoplasmosis. However, in many situations, IL-10 is not produced by Th1 cells in response to antigenic stimulation. Our goal was to address the molecular signals that determine whether Th1 cells develop to produce IL-10 (Trinchieri, 2007). Here, we showed that Th1 cells required high-antigen-dose-induced ERK1 and ERK2 phosphorylation and IL-12-induced STAT-4 activation to produce IL-10. Our findings that ERK1 and ERK2 activation was a common pathway required for the production of IL-10 by Th1, Th2, and Th17 cell subsets, which differentiate along distinct pathways, such that IL-10 provides a highly regulated feedback loop to avoid the extremes of excessive inflammation or chronic infections and also allow a protective response to diverse pathogens. \nIn certain viral or parasitic infections (Anderson etal., 2007; Brooks etal., 2006; Ejrnaes etal., 2006), high amounts of stimulation may lead to the chronic nonhealing infection shown to be regulated by IL-10. During the course of infection, after initial triggering with antigen, Tcells migrate to the tissue encountering high doses of antigen and factors produced by the innate immune response. Under these conditions, we speculate that Th1 cells will be induced to express high amounts of IL-10, in keeping with reports that IL-10-producing Th1 cells were found in CD4+ clones isolated from BAL but not blood of TB patients (Gerosa etal., 1999). Similarly, the immune response to a clinical isolate of L. major, which produces heavily infected nonhealing lesions, was found to be regulated by IL-10 derived from Foxp3- Th1 cells that coproduce IL-10 and IFN-gamma (Anderson etal., 2007), and the immune response during T. gondii infection was found also to be regulated by Foxp3- Th1 cells (Jankovic etal., 2007). It is likely that IL-10 production by Th1 cells is evoked under conditions of high inflammation and antigenic stimulation, whereas regulatory CD4+ Tcells producing IL-10 may operate to regulate the immune response under conditions in which the pathogen is clinically controlled, such as in infection with L. major (Friedlin strain) (Belkaid etal., 2002; Suffia etal., 2006). We now also reported that CD4+ Tcells cultured with high antigen dose and IL-12 differentiate into canonical Th1 effector cells , which, in addition to expressing large amounts of IFN-gamma and IL-10, lose their IL-2 expression as described before in certain chronic infection models (Sallusto etal., 2004). Our demonstration that loss of IL-2 is accompanied by production of IL-10 offers potential additional mechanisms whereby effector Tcell responses may be dampened during chronic disease. \nUsing an invivo transfer model of DO11.10 TCR transgenic cells (Castro etal., 2000), we showed that IL-10-producing Th1 cells were differentiated in the presence of high doses of OVA protein and LPS. We showed here that this induction of IL-10 inTh1 cells invivo was markedly, but not totally, reduced in STAT4-deficient Tcells as observed during T. gondii infection (Jankovic etal., 2002). A high antigenic activation during T. gondii infection or high antigen doses delivered in the presence of LPS, as seen in our system, may compensate for an absolute requirement for IL-12 in the induction of IL-10 by Th1 cells. \nIn our invitro system, repeated stimulation of Th1 cells with high antigen doses allowed the development of Th1 cells producing IL-10 in an IL-12-dependent manner. IL-10 production by Th1 cells induced by high antigen dose and IL-12 was independent of IFN-gamma, in keeping with previous findings (Jankovic etal., 2002). However, a role for IFN-gamma in mediating IL-10 reactivation by Th1 cells during secondary infection with T. gondii has been suggested (Shaw etal., 2006). We have found that CD4+ Tcells exposed to a high dose of antigen do not express IL-10 upon restimulation, but can be induced to produce IL-10 upon re-exposure to a high dose of antigen in the recall phase in the absence of added IL-12. However, this is dependent on the induction of IL-12 by antigen-presenting DCs. The combination of both high antigen dose and IL-12 resulted in the highest levels of IL-10 production and correlated with the high levels of ERK1 and ERK2 activation. The increased expression of IFN-gamma observed during the secondary phase will induce increased IL-12 production by DCs and suggests that repeated high-level TCR activation feeds back to upregulate IL-12 production by DC. It is thus likely that in T. gondii infection invivo (Shaw etal., 2006), the requirement for IFN-gamma to induce IL-10, was for feedback upregulation of IL-12 by DCs, which in turn induced IL-10 in the Th1 cells. \nAlthough IL-10 may be differentially regulated in Th1 and Th2 cells as has been reported (Chang etal., 2007; Wang etal., 2005), some studies suggest the existence of common pathways, but the molecular basis for these is as yet unclear. Costimulatory OX-40 signals have been shown to negatively regulate IL-10 production (Ito etal., 2005) both in Th1 and Th2 cells, whereas ICOS signaling has been suggested to induce IL-10 (Ito etal., 2007; Witsch etal., 2002) in both Th1 and Th2 cells. However, in some cases, ICOS signaling also regulates IL-4 production and Th2 responses (Greenwald etal., 2005). We now provide a common mechanism of ERK1 and ERK2 activation for the regulation of IL-10 production in Th1, Th2, and Th17 cells, although each subset differentiates along a distinct and subset-specific transcriptional pathway. This reinforces the fact that IL-10 is not a Th cell-subset-specific cytokine, but instead is produced in a tightly regulated fashion during each differentiation pathway. Of note, a role for ERK1 and ERK2 activation in the induction of IL-10 production has already been described for macrophages and DC (Agrawal etal., 2006; Hacker etal., 1999). \nDifferential transcriptional regulation of IL-10 in Th1 and Th2 cells has been suggested (Chang etal., 2007; Wang etal., 2005), and extensive histone acetylation of the IL-10 gene is detectable in fully polarized Th2 cells, but not Th1cells (Chang etal., 2007). We provide evidence that IL-10 is produced in canonical Th1 cells and that its expression correlates with the expression of T-bet and the highest IFN-gamma production, in keeping with our observations that high-dose antigen stimulation and IL-12 signaling are required for IL-10 and IFN-gamma expression. It has also been shown that maintenance of IL-10 expression is conditional on IL-12 or IL-4 unless the IL-10 gene is imprinted by GATA-3 (Chang etal., 2007), which can remodel the IL-10 locus, thus explaining the highest amounts of IL-10 produced by Th2 cells (Chang etal., 2007; Shoemaker etal., 2006). We show here that high antigen dose and IL-12 drastically downregulate Gata-3 expression, suggesting that additional factors are in place to induce IL-10 expression in Th1 cells, albeit transiently. Expression of c-maf was greatly diminished by high antigen doses in Tcells and yet was unexpectedly maintained by IL-12 and present in Th17 cells. That c-maf expression is common to IL-10-producing Th1, Th2, and Th17 cells and, like IL-10, is dependent on ERK activation in Th1 and Th17 cells for its expression is of interest because c-Maf has been shown to be an essential transcription factor for IL-10 expression in macrophages (Cao etal., 2005). \nIn summary, we show that although Th1, Th2, and Th17 CD4+ Tcell subsets differentiate along distinct signaling and transcriptional pathways, they can all be induced to make IL-10. ERK1 and ERK2 activation is required for IL-10 production by all these Th cell subsets. With regard to the expression of IL-10 by Th1 cells, our data provide a mechanism for how IL-10 expression is induced and then amplified and regulated by the levels of antigen and IL-12 encountered in the environment. This provides a mechanism whereby a Th1 cell responds to extrinsic signals, reflecting increased inflammation in the tissue, to tightly regulate the production of IL-10 so as to allow a protective response to eradicate a pathogen with minimal damage to the host and also prevent chronic infection. Moreover, our findings have important implications for the regulation of IL-10 production during an inflammatory Th1 response in infection and may be of relevance for the design of vaccines and for strategies in immunotherapy in infectious diseases. \n" ], "offsets": [ [ 0, 8707 ] ] } ]

[ { "id": "PMC-2791889-09-Discussion_T1", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 11, 16 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T2", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 208, 213 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T3", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 353, 358 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T4", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 524, 529 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T5", "type": "Protein", "text": [ "ERK1" ], "offsets": [ [ 616, 620 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T6", "type": "Protein", "text": [ "ERK2" ], "offsets": [ [ 625, 629 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T7", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 650, 655 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T8", "type": "Protein", "text": [ "STAT-4" ], "offsets": [ [ 664, 670 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T9", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 693, 698 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T10", "type": "Protein", "text": [ "ERK1" ], "offsets": [ [ 718, 722 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T11", "type": "Protein", "text": [ "ERK2" ], "offsets": [ [ 727, 731 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T12", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 795, 800 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T13", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 892, 897 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T14", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1274, 1279 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T15", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1563, 1568 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T16", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1599, 1604 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T17", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1639, 1642 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T18", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1867, 1872 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T19", "type": "Protein", "text": [ "Foxp3" ], "offsets": [ [ 1886, 1891 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T20", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1918, 1923 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T21", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1928, 1937 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T22", "type": "Protein", "text": [ "Foxp3" ], "offsets": [ [ 2047, 2052 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T23", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 2106, 2111 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T24", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 2230, 2233 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T25", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 2252, 2257 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T26", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 2489, 2492 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T27", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 2537, 2542 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T28", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 2643, 2652 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T29", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 2657, 2662 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T30", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 2675, 2679 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T31", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 2802, 2806 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T32", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 2839, 2844 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T33", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 3058, 3063 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T34", "type": "Protein", "text": [ "OVA" ], "offsets": [ [ 3137, 3140 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T35", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 3196, 3201 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T36", "type": "Protein", "text": [ "STAT4" ], "offsets": [ [ 3263, 3268 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T37", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 3530, 3535 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T38", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 3556, 3561 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T39", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 3705, 3710 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T40", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 3717, 3722 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T41", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 3741, 3746 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T42", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 3804, 3809 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T43", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 3829, 3838 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T44", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 3918, 3927 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T45", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 3941, 3946 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T46", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 4073, 4076 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T47", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 4134, 4139 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T48", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 4190, 4195 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T49", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 4283, 4288 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T50", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 4337, 4342 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T51", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 4416, 4421 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T52", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 4456, 4461 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T53", "type": "Protein", "text": [ "ERK1" ], "offsets": [ [ 4512, 4516 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T54", "type": "Protein", "text": [ "ERK2" ], "offsets": [ [ 4521, 4525 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T55", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 4566, 4575 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T56", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 4634, 4639 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T57", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 4736, 4741 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T58", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 4853, 4862 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T59", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 4873, 4878 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T60", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 4913, 4918 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T61", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 4949, 4954 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T62", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 4983, 4988 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T63", "type": "Protein", "text": [ "OX-40" ], "offsets": [ [ 5224, 5229 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T64", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 5277, 5282 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T65", "type": "Protein", "text": [ "ICOS" ], "offsets": [ [ 5347, 5351 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T66", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 5391, 5396 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T67", "type": "Protein", "text": [ "ICOS" ], "offsets": [ [ 5486, 5490 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T68", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 5516, 5520 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T69", "type": "Protein", "text": [ "ERK1" ], "offsets": [ [ 5612, 5616 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T70", "type": "Protein", "text": [ "ERK2" ], "offsets": [ [ 5621, 5625 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T71", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 5659, 5664 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T72", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 5833, 5838 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T73", "type": "Protein", "text": [ "ERK1" ], "offsets": [ [ 5994, 5998 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T74", "type": "Protein", "text": [ "ERK2" ], "offsets": [ [ 6003, 6007 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T75", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 6039, 6044 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T76", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 6193, 6198 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T77", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 6292, 6299 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T78", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 6319, 6324 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T79", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 6437, 6442 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T80", "type": "Protein", "text": [ "T-bet" ], "offsets": [ [ 6536, 6541 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T81", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 6558, 6567 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T82", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 6652, 6657 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T83", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 6685, 6690 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T84", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 6695, 6704 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T85", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 6760, 6765 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T86", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 6795, 6800 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T87", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 6804, 6808 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T88", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 6820, 6825 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T89", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 6847, 6853 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T90", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 6897, 6902 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T91", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 6949, 6954 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T92", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 7061, 7066 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T93", "type": "Protein", "text": [ "Gata-3" ], "offsets": [ [ 7092, 7098 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T94", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 7169, 7174 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T95", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 7234, 7239 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T96", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 7334, 7339 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T97", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 7372, 7377 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T98", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 7402, 7407 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T99", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 7453, 7458 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T100", "type": "Protein", "text": [ "ERK" ], "offsets": [ [ 7476, 7479 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T101", "type": "Protein", "text": [ "c-Maf" ], "offsets": [ [ 7555, 7560 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T102", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 7620, 7625 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T103", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 7725, 7728 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T104", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 7845, 7850 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T105", "type": "Protein", "text": [ "ERK1" ], "offsets": [ [ 7852, 7856 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T106", "type": "Protein", "text": [ "ERK2" ], "offsets": [ [ 7861, 7865 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T107", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 7893, 7898 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T108", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 7973, 7978 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T109", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 8030, 8035 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T110", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 8120, 8125 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T111", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 8321, 8326 ] ], "normalized": [] }, { "id": "PMC-2791889-09-Discussion_T112", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 8529, 8534 ] ], "normalized": [] } ]

[ { "id": "PMC-2791889-09-Discussion_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 17, 27 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T1" } ] }, { "id": "PMC-2791889-09-Discussion_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 214, 224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T2" } ] }, { "id": "PMC-2791889-09-Discussion_E3", "type": "Gene_expression", "trigger": { "text": [ "produced" ], "offsets": [ [ 366, 374 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T3" } ] }, { "id": "PMC-2791889-09-Discussion_E4", "type": "Positive_regulation", "trigger": { "text": [ "in response to" ], "offsets": [ [ 388, 402 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E3" } ] }, { "id": "PMC-2791889-09-Discussion_E5", "type": "Gene_expression", "trigger": { "text": [ "produce" ], "offsets": [ [ 516, 523 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T4" } ] }, { "id": "PMC-2791889-09-Discussion_E6", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 581, 589 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E7" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_E8" } ] }, { "id": "PMC-2791889-09-Discussion_E9", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 581, 589 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E7" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_E10" } ] }, { "id": "PMC-2791889-09-Discussion_E11", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 581, 589 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E7" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_E12" } ] }, { "id": "PMC-2791889-09-Discussion_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 630, 645 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T5" } ] }, { "id": "PMC-2791889-09-Discussion_E10", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 630, 645 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T6" } ] }, { "id": "PMC-2791889-09-Discussion_E13", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 656, 663 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E12" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T7" } ] }, { "id": "PMC-2791889-09-Discussion_E12", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 671, 681 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T8" } ] }, { "id": "PMC-2791889-09-Discussion_E7", "type": "Gene_expression", "trigger": { "text": [ "produce" ], "offsets": [ [ 685, 692 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T9" } ] }, { "id": "PMC-2791889-09-Discussion_E14", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 732, 742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T10" } ] }, { "id": "PMC-2791889-09-Discussion_E15", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 732, 742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T11" } ] }, { "id": "PMC-2791889-09-Discussion_E16", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 764, 772 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E17" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_E14" } ] }, { "id": "PMC-2791889-09-Discussion_E18", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 764, 772 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E17" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_E15" } ] }, { "id": "PMC-2791889-09-Discussion_E17", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 781, 791 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T12" } ] }, { "id": "PMC-2791889-09-Discussion_E19", "type": "Regulation", "trigger": { "text": [ "provides a highly regulated feedback loop" ], "offsets": [ [ 898, 939 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E17" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T13" } ] }, { "id": "PMC-2791889-09-Discussion_E20", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1528, 1535 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E21" } ] }, { "id": "PMC-2791889-09-Discussion_E21", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 1539, 1546 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T15" } ] }, { "id": "PMC-2791889-09-Discussion_E22", "type": "Gene_expression", "trigger": { "text": [ "producing" ], "offsets": [ [ 1605, 1614 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T16" } ] }, { "id": "PMC-2791889-09-Discussion_E23", "type": "Gene_expression", "trigger": { "text": [ "coproduce" ], "offsets": [ [ 1908, 1917 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T20" } ] }, { "id": "PMC-2791889-09-Discussion_E24", "type": "Gene_expression", "trigger": { "text": [ "coproduce" ], "offsets": [ [ 1908, 1917 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T21" } ] }, { "id": "PMC-2791889-09-Discussion_E25", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 2112, 2122 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T23" } ] }, { "id": "PMC-2791889-09-Discussion_E26", "type": "Gene_expression", "trigger": { "text": [ "producing" ], "offsets": [ [ 2242, 2251 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T25" } ] }, { "id": "PMC-2791889-09-Discussion_E27", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 2615, 2625 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T28" } ] }, { "id": "PMC-2791889-09-Discussion_E28", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 2615, 2625 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T29" } ] }, { "id": "PMC-2791889-09-Discussion_E29", "type": "Negative_regulation", "trigger": { "text": [ "lose" ], "offsets": [ [ 2664, 2668 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E30" } ] }, { "id": "PMC-2791889-09-Discussion_E30", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2680, 2690 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T30" } ] }, { "id": "PMC-2791889-09-Discussion_E31", "type": "Negative_regulation", "trigger": { "text": [ "loss" ], "offsets": [ [ 2794, 2798 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T31" } ] }, { "id": "PMC-2791889-09-Discussion_E32", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 2825, 2835 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T32" } ] }, { "id": "PMC-2791889-09-Discussion_E33", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 3183, 3192 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T35" } ] }, { "id": "PMC-2791889-09-Discussion_E34", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 3252, 3259 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E33" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_E35" } ] }, { "id": "PMC-2791889-09-Discussion_E35", "type": "Negative_regulation", "trigger": { "text": [ "deficient" ], "offsets": [ [ 3269, 3278 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T36" } ] }, { "id": "PMC-2791889-09-Discussion_E36", "type": "Positive_regulation", "trigger": { "text": [ "requirement" ], "offsets": [ [ 3514, 3525 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E37" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T37" } ] }, { "id": "PMC-2791889-09-Discussion_E37", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 3543, 3552 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T38" } ] }, { "id": "PMC-2791889-09-Discussion_E38", "type": "Gene_expression", "trigger": { "text": [ "producing" ], "offsets": [ [ 3695, 3704 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T39" } ] }, { "id": "PMC-2791889-09-Discussion_E39", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 3747, 3757 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T41" } ] }, { "id": "PMC-2791889-09-Discussion_E40", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 3771, 3778 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E39" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T42" } ] }, { "id": "PMC-2791889-09-Discussion_E41", "type": "Regulation", "trigger": { "text": [ "independent" ], "offsets": [ [ 3814, 3825 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E40" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T43" } ] }, { "id": "PMC-2791889-09-Discussion_E42", "type": "Positive_regulation", "trigger": { "text": [ "mediating" ], "offsets": [ [ 3931, 3940 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E43" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T44" } ] }, { "id": "PMC-2791889-09-Discussion_E43", "type": "Positive_regulation", "trigger": { "text": [ "reactivation" ], "offsets": [ [ 3947, 3959 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T45" } ] }, { "id": "PMC-2791889-09-Discussion_E44", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 4126, 4133 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T47" } ] }, { "id": "PMC-2791889-09-Discussion_E45", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 4171, 4178 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E46" } ] }, { "id": "PMC-2791889-09-Discussion_E46", "type": "Gene_expression", "trigger": { "text": [ "produce" ], "offsets": [ [ 4182, 4189 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T48" } ] }, { "id": "PMC-2791889-09-Discussion_E47", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 4307, 4316 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E45" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_E48" } ] }, { "id": "PMC-2791889-09-Discussion_E48", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 4324, 4333 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T50" } ] }, { "id": "PMC-2791889-09-Discussion_E49", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 4422, 4430 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E50" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T51" } ] }, { "id": "PMC-2791889-09-Discussion_E50", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 4462, 4472 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T52" } ] }, { "id": "PMC-2791889-09-Discussion_E51", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 4526, 4536 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T53" } ] }, { "id": "PMC-2791889-09-Discussion_E52", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 4526, 4536 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T54" } ] }, { "id": "PMC-2791889-09-Discussion_E53", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 4542, 4551 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E54" } ] }, { "id": "PMC-2791889-09-Discussion_E54", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 4552, 4562 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T55" } ] }, { "id": "PMC-2791889-09-Discussion_E55", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 4617, 4623 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E56" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_E53" } ] }, { "id": "PMC-2791889-09-Discussion_E56", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 4624, 4633 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E57" } ] }, { "id": "PMC-2791889-09-Discussion_E57", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 4640, 4650 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T56" } ] }, { "id": "PMC-2791889-09-Discussion_E58", "type": "Positive_regulation", "trigger": { "text": [ "upregulate" ], "offsets": [ [ 4725, 4735 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E59" } ] }, { "id": "PMC-2791889-09-Discussion_E59", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 4742, 4752 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T57" } ] }, { "id": "PMC-2791889-09-Discussion_E60", "type": "Positive_regulation", "trigger": { "text": [ "requirement" ], "offsets": [ [ 4837, 4848 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E61" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T58" } ] }, { "id": "PMC-2791889-09-Discussion_E61", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 4866, 4872 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T59" } ] }, { "id": "PMC-2791889-09-Discussion_E62", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 4897, 4909 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T60" } ] }, { "id": "PMC-2791889-09-Discussion_E63", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 4941, 4948 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T61" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_E62" } ] }, { "id": "PMC-2791889-09-Discussion_E64", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 5011, 5020 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T62" } ] }, { "id": "PMC-2791889-09-Discussion_E65", "type": "Negative_regulation", "trigger": { "text": [ "negatively regulate" ], "offsets": [ [ 5257, 5276 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E66" } ] }, { "id": "PMC-2791889-09-Discussion_E66", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 5283, 5293 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T64" } ] }, { "id": "PMC-2791889-09-Discussion_E67", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 5384, 5390 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T66" } ] }, { "id": "PMC-2791889-09-Discussion_E68", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 5506, 5515 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E69" } ] }, { "id": "PMC-2791889-09-Discussion_E69", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 5521, 5531 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T68" } ] }, { "id": "PMC-2791889-09-Discussion_E70", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 5626, 5636 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T69" } ] }, { "id": "PMC-2791889-09-Discussion_E71", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 5626, 5636 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T70" } ] }, { "id": "PMC-2791889-09-Discussion_E72", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 5645, 5655 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E73" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T69" } ] }, { "id": "PMC-2791889-09-Discussion_E74", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 5645, 5655 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E73" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T70" } ] }, { "id": "PMC-2791889-09-Discussion_E73", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 5665, 5675 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T71" } ] }, { "id": "PMC-2791889-09-Discussion_E75", "type": "Gene_expression", "trigger": { "text": [ "produced" ], "offsets": [ [ 5897, 5905 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T72" } ] }, { "id": "PMC-2791889-09-Discussion_E76", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 5919, 5928 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E75" } ] }, { "id": "PMC-2791889-09-Discussion_E77", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 5985, 5989 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E78" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_E79" } ] }, { "id": "PMC-2791889-09-Discussion_E80", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 5985, 5989 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E78" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_E81" } ] }, { "id": "PMC-2791889-09-Discussion_E79", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 6008, 6018 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T73" } ] }, { "id": "PMC-2791889-09-Discussion_E81", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 6008, 6018 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T74" } ] }, { "id": "PMC-2791889-09-Discussion_E78", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 6026, 6035 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E82" } ] }, { "id": "PMC-2791889-09-Discussion_E82", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 6045, 6055 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T75" } ] }, { "id": "PMC-2791889-09-Discussion_E83", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 6179, 6189 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T76" } ] }, { "id": "PMC-2791889-09-Discussion_E84", "type": "Gene_expression", "trigger": { "text": [ "produced" ], "offsets": [ [ 6446, 6454 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T79" } ] }, { "id": "PMC-2791889-09-Discussion_E85", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 6491, 6501 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T79" } ] }, { "id": "PMC-2791889-09-Discussion_E86", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 6522, 6532 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T80" } ] }, { "id": "PMC-2791889-09-Discussion_E87", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 6568, 6578 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T81" } ] }, { "id": "PMC-2791889-09-Discussion_E88", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 6672, 6680 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E89" } ] }, { "id": "PMC-2791889-09-Discussion_E90", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 6672, 6680 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E91" } ] }, { "id": "PMC-2791889-09-Discussion_E89", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 6705, 6715 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T83" } ] }, { "id": "PMC-2791889-09-Discussion_E91", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 6705, 6715 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T84" } ] }, { "id": "PMC-2791889-09-Discussion_E92", "type": "Positive_regulation", "trigger": { "text": [ "maintenance" ], "offsets": [ [ 6745, 6756 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E93" } ] }, { "id": "PMC-2791889-09-Discussion_E93", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 6766, 6776 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T85" } ] }, { "id": "PMC-2791889-09-Discussion_E94", "type": "Positive_regulation", "trigger": { "text": [ "conditional" ], "offsets": [ [ 6780, 6791 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E92" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T86" } ] }, { "id": "PMC-2791889-09-Discussion_E95", "type": "Positive_regulation", "trigger": { "text": [ "conditional" ], "offsets": [ [ 6780, 6791 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E92" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T87" } ] }, { "id": "PMC-2791889-09-Discussion_E96", "type": "Gene_expression", "trigger": { "text": [ "produced" ], "offsets": [ [ 6955, 6963 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T91" } ] }, { "id": "PMC-2791889-09-Discussion_E97", "type": "Negative_regulation", "trigger": { "text": [ "downregulate" ], "offsets": [ [ 7079, 7091 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E98" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T92" } ] }, { "id": "PMC-2791889-09-Discussion_E98", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 7099, 7109 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T93" } ] }, { "id": "PMC-2791889-09-Discussion_E99", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 7162, 7168 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E100" } ] }, { "id": "PMC-2791889-09-Discussion_E100", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 7175, 7185 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T94" } ] }, { "id": "PMC-2791889-09-Discussion_E101", "type": "Gene_expression", "trigger": { "text": [ "Expression" ], "offsets": [ [ 7220, 7230 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T95" } ] }, { "id": "PMC-2791889-09-Discussion_E102", "type": "Negative_regulation", "trigger": { "text": [ "diminished" ], "offsets": [ [ 7252, 7262 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E101" } ] }, { "id": "PMC-2791889-09-Discussion_E103", "type": "Positive_regulation", "trigger": { "text": [ "maintained" ], "offsets": [ [ 7320, 7330 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E101" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T96" } ] }, { "id": "PMC-2791889-09-Discussion_E104", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 7378, 7388 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T97" } ] }, { "id": "PMC-2791889-09-Discussion_E105", "type": "Gene_expression", "trigger": { "text": [ "producing" ], "offsets": [ [ 7408, 7417 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T98" } ] }, { "id": "PMC-2791889-09-Discussion_E106", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 7463, 7472 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E104" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_E107" } ] }, { "id": "PMC-2791889-09-Discussion_E108", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 7463, 7472 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T99" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_E107" } ] }, { "id": "PMC-2791889-09-Discussion_E107", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 7480, 7490 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T100" } ] }, { "id": "PMC-2791889-09-Discussion_E109", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 7521, 7531 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T97" } ] }, { "id": "PMC-2791889-09-Discussion_E110", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 7585, 7594 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E111" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T101" } ] }, { "id": "PMC-2791889-09-Discussion_E111", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 7626, 7636 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T102" } ] }, { "id": "PMC-2791889-09-Discussion_E112", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 7829, 7836 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E113" } ] }, { "id": "PMC-2791889-09-Discussion_E113", "type": "Gene_expression", "trigger": { "text": [ "make" ], "offsets": [ [ 7840, 7844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T104" } ] }, { "id": "PMC-2791889-09-Discussion_E114", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 7866, 7876 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T105" } ] }, { "id": "PMC-2791889-09-Discussion_E115", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 7866, 7876 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T106" } ] }, { "id": "PMC-2791889-09-Discussion_E116", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 7880, 7888 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E117" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T105" } ] }, { "id": "PMC-2791889-09-Discussion_E118", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 7880, 7888 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E117" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T106" } ] }, { "id": "PMC-2791889-09-Discussion_E117", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 7899, 7909 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T107" } ] }, { "id": "PMC-2791889-09-Discussion_E119", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 7959, 7969 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T108" } ] }, { "id": "PMC-2791889-09-Discussion_E120", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 8036, 8046 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T109" } ] }, { "id": "PMC-2791889-09-Discussion_E121", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 8050, 8057 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E120" } ] }, { "id": "PMC-2791889-09-Discussion_E122", "type": "Positive_regulation", "trigger": { "text": [ "amplified" ], "offsets": [ [ 8067, 8076 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E120" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T110" } ] }, { "id": "PMC-2791889-09-Discussion_E123", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 8081, 8090 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E120" }, { "role": "Cause", "ref_id": "PMC-2791889-09-Discussion_T110" } ] }, { "id": "PMC-2791889-09-Discussion_E124", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 8294, 8302 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E125" } ] }, { "id": "PMC-2791889-09-Discussion_E125", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 8307, 8317 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T111" } ] }, { "id": "PMC-2791889-09-Discussion_E126", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 8515, 8525 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_E127" } ] }, { "id": "PMC-2791889-09-Discussion_E127", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 8535, 8545 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-09-Discussion_T112" } ] } ]

[]

[]

[ { "id": "PMC-2791889-10-Experimental_Procedures-01__text", "type": "abstract", "text": [ "Mice, Cytokines, Antibodies, and Other Reagents\nBALB/c DO11.10 mice transgenic for OVA-specific TCR WT or crossed back with Rag1-, IL-4-,IFN-gamma-, STAT4-, and STAT6-deficient mice were used as a source of antigen-specific Tcells (Murphy etal., 1990; Ouyang etal., 1998; Shoemaker etal., 2006) and were bred and maintained under SPF conditions at the NIMR, London, Home Office, UK, Animals (Scientific Procedures) Act 1986 or at the Washington University School of Medicine. Female mice were used at 8-12 weeks old, and animal protocols were approved according to the Animals (Scientific Procedures) Act 1986, Home Office, UK. Reagents, including antibodies for Tcell and DC preparation, purification and culture, media, cytokines, and cytokine mAbs have been described (Hosken etal., 1995; Shoemaker etal., 2006; Veldhoen etal., 2009; Veldhoen etal., 2006). LPS (S. minnesota) was from Alexis, chicken ovalbumin protein (OVA protein) was from from Sigma-Aldrich, and ovalbumin peptide323-339 (OVA) (endotoxin-free) was from Biosynthesis. U0126 was from BioMol International. PD184352 (MEK inhibitors), SB203580 (p38 inhibitor), and CT99021 (GSK3beta inhibitor) were kind gifts from P. Cohen and N.Shpiro, University of Dundee, UK. \n" ], "offsets": [ [ 0, 1234 ] ] } ]

[ { "id": "PMC-2791889-10-Experimental_Procedures-01_T1", "type": "Protein", "text": [ "OVA" ], "offsets": [ [ 83, 86 ] ], "normalized": [] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_T2", "type": "Protein", "text": [ "Rag1" ], "offsets": [ [ 124, 128 ] ], "normalized": [] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_T3", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 131, 135 ] ], "normalized": [] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_T4", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 137, 146 ] ], "normalized": [] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_T5", "type": "Protein", "text": [ "STAT4" ], "offsets": [ [ 149, 154 ] ], "normalized": [] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_T6", "type": "Protein", "text": [ "STAT6" ], "offsets": [ [ 161, 166 ] ], "normalized": [] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_T7", "type": "Protein", "text": [ "ovalbumin" ], "offsets": [ [ 904, 913 ] ], "normalized": [] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_T8", "type": "Protein", "text": [ "OVA" ], "offsets": [ [ 923, 926 ] ], "normalized": [] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_T9", "type": "Protein", "text": [ "ovalbumin" ], "offsets": [ [ 969, 978 ] ], "normalized": [] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_T10", "type": "Protein", "text": [ "MEK" ], "offsets": [ [ 1087, 1090 ] ], "normalized": [] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_T11", "type": "Protein", "text": [ "p38" ], "offsets": [ [ 1114, 1117 ] ], "normalized": [] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_T12", "type": "Protein", "text": [ "GSK3beta" ], "offsets": [ [ 1143, 1151 ] ], "normalized": [] } ]

[ { "id": "PMC-2791889-10-Experimental_Procedures-01_E1", "type": "Negative_regulation", "trigger": { "text": [ "deficient" ], "offsets": [ [ 167, 176 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-10-Experimental_Procedures-01_T2" } ] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_E2", "type": "Negative_regulation", "trigger": { "text": [ "deficient" ], "offsets": [ [ 167, 176 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-10-Experimental_Procedures-01_T3" } ] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_E3", "type": "Negative_regulation", "trigger": { "text": [ "deficient" ], "offsets": [ [ 167, 176 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-10-Experimental_Procedures-01_T4" } ] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_E4", "type": "Negative_regulation", "trigger": { "text": [ "deficient" ], "offsets": [ [ 167, 176 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-10-Experimental_Procedures-01_T5" } ] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_E5", "type": "Negative_regulation", "trigger": { "text": [ "deficient" ], "offsets": [ [ 167, 176 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-10-Experimental_Procedures-01_T6" } ] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibitors" ], "offsets": [ [ 1091, 1101 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-10-Experimental_Procedures-01_T10" } ] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 1118, 1127 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-10-Experimental_Procedures-01_T11" } ] }, { "id": "PMC-2791889-10-Experimental_Procedures-01_E8", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 1152, 1161 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-10-Experimental_Procedures-01_T12" } ] } ]

[ { "id": "PMC-2791889-10-Experimental_Procedures-01_1", "entity_ids": [ "PMC-2791889-10-Experimental_Procedures-01_T7", "PMC-2791889-10-Experimental_Procedures-01_T8" ] } ]

[]

[ { "id": "PMC-2791889-11-Experimental_Procedures-02__text", "type": "abstract", "text": [ "Isolation of CD4+ T Cells and of Splenic DC and Cell Culture for T Cell Phenotype Differentiation\nT cells were sorted for CD4+CD62Lhi, CD4+CD62LhiCD25-, or CD4+CD44loCD25- to >98% on a Moflo cytometer (Cytomation) as before (Shoemaker etal., 2006; Veldhoen etal., 2009). In most cases, experiments were reproduced with each type of purified CD4+ Tcell population with similar results obtained. Splenic DCs were prepared as described (Hosken etal., 1995), and sort purified CD11c+ cells were added to the Tcell culture. Purified DO11.10 CD4+ Tcells (1 x 105 cells/ml) were cultured as before (Hosken etal., 1995), in a total volume of 1 ml cRPMI medium in a 48-well plate, with splenic DCs (2 x 104 cells/ml), and varying amounts of OVA and of IL-12. APC-independent differentiation of naive CD4+ Tcells into Th1 and Th2 cells used stimulation with anti-CD3 and anti-CD28 and appropriate cytokine conditions, and control Th1 and Th2 cells were cultured as described before (Hosken etal., 1995; Shoemaker etal., 2006). Culture conditions for Th17 cells were as described before (Veldhoen etal., 2006). Importantly, Th1 and Th2 cells could be differentiated in cRPMI or IMDM (Hosken etal., 1995; Shoemaker etal., 2006; Veldhoen etal., 2006), but Th17 cells were only differentiated optimally in IMDM (Veldhoen etal., 2009). When indicated, U0126 or PD184352 (MEK inhibitors), SB203580 (p38 inhibitor), CT99021 (GSK3beta inhibitor), or a similar amount of DMSO were present in the culture. More details of specific culture conditions are provided in Figures S6 and S7. \n" ], "offsets": [ [ 0, 1566 ] ] } ]

[ { "id": "PMC-2791889-11-Experimental_Procedures-02_T1", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 13, 16 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T2", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 122, 125 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T3", "type": "Protein", "text": [ "CD62L" ], "offsets": [ [ 126, 131 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T4", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 135, 138 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T5", "type": "Protein", "text": [ "CD62L" ], "offsets": [ [ 139, 144 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T6", "type": "Protein", "text": [ "CD25" ], "offsets": [ [ 146, 150 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T7", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 156, 159 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T8", "type": "Protein", "text": [ "CD44" ], "offsets": [ [ 160, 164 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T9", "type": "Protein", "text": [ "CD25" ], "offsets": [ [ 166, 170 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T10", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 341, 344 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T11", "type": "Protein", "text": [ "CD11c" ], "offsets": [ [ 473, 478 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T12", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 536, 539 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T13", "type": "Protein", "text": [ "OVA" ], "offsets": [ [ 732, 735 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T14", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 743, 748 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T15", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 791, 794 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T16", "type": "Protein", "text": [ "CD3" ], "offsets": [ [ 853, 856 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T17", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 866, 870 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T18", "type": "Protein", "text": [ "MEK" ], "offsets": [ [ 1356, 1359 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T19", "type": "Protein", "text": [ "p38" ], "offsets": [ [ 1383, 1386 ] ], "normalized": [] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_T20", "type": "Protein", "text": [ "GSK3beta" ], "offsets": [ [ 1408, 1416 ] ], "normalized": [] } ]

[ { "id": "PMC-2791889-11-Experimental_Procedures-02_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibitors" ], "offsets": [ [ 1360, 1370 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-11-Experimental_Procedures-02_T18" } ] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 1387, 1396 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-11-Experimental_Procedures-02_T19" } ] }, { "id": "PMC-2791889-11-Experimental_Procedures-02_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 1417, 1426 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-11-Experimental_Procedures-02_T20" } ] } ]

[]

[]

[ { "id": "PMC-2791889-12-Experimental_Procedures-03__text", "type": "abstract", "text": [ "Cytokine Detection by ICS and ELISA\nAt day 5 or 7, cells were restimulated with immobilized anti-CD3 (2 mug/ml) and anti-CD28 (2 mug/ml) (4 hr with BrefeldinA [10 mug/ml] in the last 2 hr) or with PdBU and Ionomycin (5 hr with BrefeldinA [1 mug/ml]). After ICS FACS, data were collected on a FACSCalibur (Becton Dickinson) and analyzed with FlowJo (Tree Star). For ELISA, cells were similarly restimulated for 48 hr and supernatant was collected and analyzed for IL-4, IL-10, and IFN-gamma as described before (Shoemaker etal., 2006). \n" ], "offsets": [ [ 0, 536 ] ] } ]

[ { "id": "PMC-2791889-12-Experimental_Procedures-03_T1", "type": "Protein", "text": [ "CD3" ], "offsets": [ [ 97, 100 ] ], "normalized": [] }, { "id": "PMC-2791889-12-Experimental_Procedures-03_T2", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 121, 125 ] ], "normalized": [] }, { "id": "PMC-2791889-12-Experimental_Procedures-03_T3", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 463, 467 ] ], "normalized": [] }, { "id": "PMC-2791889-12-Experimental_Procedures-03_T4", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 469, 474 ] ], "normalized": [] }, { "id": "PMC-2791889-12-Experimental_Procedures-03_T5", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 480, 489 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMC-2791889-13-Experimental_Procedures-04__text", "type": "abstract", "text": [ "In Vivo Studies\nBALB/c mice were injected intravenously (i.v.) with a red blood cell-depleted single-cell spleen suspension (2.5 x 107 cells) (Castro etal., 2000) from DO11.10 WT or STAT-deficient mice. After 48 hr, they were injected subcutaneously with PBS or with OVA protein (5 mg) plus LPS (5 mug). The inguinal lymph nodes were removed 48 hr later. A single-cell suspension (1 x 106 cells) was restimulated for 24 or 48 hr with 1 muM or 3 muM of OVA and with BrefeldinA for the last 6 hr. Half of the supernatant was removed before the addition of BrefeldinA for use in an ELISA assay. The cells were fixed and stained as before. Those positive for KJ1-26-Bio and for CD4-PerCP were gated, and IFN-gamma and IL-10 staining was examined for this population and analyzed as before. \n" ], "offsets": [ [ 0, 787 ] ] } ]

[ { "id": "PMC-2791889-13-Experimental_Procedures-04_T1", "type": "Protein", "text": [ "STAT" ], "offsets": [ [ 182, 186 ] ], "normalized": [] }, { "id": "PMC-2791889-13-Experimental_Procedures-04_T2", "type": "Protein", "text": [ "OVA" ], "offsets": [ [ 267, 270 ] ], "normalized": [] }, { "id": "PMC-2791889-13-Experimental_Procedures-04_T3", "type": "Protein", "text": [ "OVA" ], "offsets": [ [ 452, 455 ] ], "normalized": [] }, { "id": "PMC-2791889-13-Experimental_Procedures-04_T4", "type": "Protein", "text": [ "KJ1-26" ], "offsets": [ [ 655, 661 ] ], "normalized": [] }, { "id": "PMC-2791889-13-Experimental_Procedures-04_T5", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 674, 677 ] ], "normalized": [] }, { "id": "PMC-2791889-13-Experimental_Procedures-04_T6", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 700, 709 ] ], "normalized": [] }, { "id": "PMC-2791889-13-Experimental_Procedures-04_T7", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 714, 719 ] ], "normalized": [] } ]

[ { "id": "PMC-2791889-13-Experimental_Procedures-04_E1", "type": "Negative_regulation", "trigger": { "text": [ "deficient" ], "offsets": [ [ 187, 196 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-13-Experimental_Procedures-04_T1" } ] } ]

[]

[]

[ { "id": "PMC-2791889-14-Experimental_Procedures-05__text", "type": "abstract", "text": [ "Real-Time Quantitative RT-PCR\nCells were harvested and restimulated in the presence of immobilized anti-CD3 (2 mug/ml) plus anti-CD28 (2 mug/ml) for 3 hr or immediately lysed. RNA was extracted and reverse-transcribed and cDNA was analyzed for the expression of cytokines and transcription factors by real-time PCR assay as before (Shoemaker etal., 2006). Target gene mRNA expression was quantified either with SYBR Green (Applied Biosystems) or with Master Mix (Applied Biosystems) and normalized to ubiquitin or HPRT mRNA levels, respectively. \n" ], "offsets": [ [ 0, 547 ] ] } ]

[ { "id": "PMC-2791889-14-Experimental_Procedures-05_T1", "type": "Protein", "text": [ "CD3" ], "offsets": [ [ 104, 107 ] ], "normalized": [] }, { "id": "PMC-2791889-14-Experimental_Procedures-05_T2", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 129, 133 ] ], "normalized": [] }, { "id": "PMC-2791889-14-Experimental_Procedures-05_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 501, 510 ] ], "normalized": [] }, { "id": "PMC-2791889-14-Experimental_Procedures-05_T4", "type": "Protein", "text": [ "HPRT" ], "offsets": [ [ 514, 518 ] ], "normalized": [] } ]

[ { "id": "PMC-2791889-14-Experimental_Procedures-05_E1", "type": "Transcription", "trigger": { "text": [ "mRNA levels" ], "offsets": [ [ 519, 530 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-14-Experimental_Procedures-05_T3" } ] }, { "id": "PMC-2791889-14-Experimental_Procedures-05_E2", "type": "Transcription", "trigger": { "text": [ "mRNA levels" ], "offsets": [ [ 519, 530 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMC-2791889-14-Experimental_Procedures-05_T4" } ] } ]

[]

[]

[ { "id": "PMC-2791889-15-Experimental_Procedures-06__text", "type": "abstract", "text": [ "Immunoblotting\nDifferentiated CD4+ Tcells were rested for 5 hr in 1% FCS-containing medium and restimulated as described for specific experiments. Cell lysates were prepared, equal amounts of protein were separated by SDS-PAGE, and phosphorylated or total ERK and actin were detected as described before (Beinke etal., 2004). \n" ], "offsets": [ [ 0, 327 ] ] } ]

[ { "id": "PMC-2791889-15-Experimental_Procedures-06_T1", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 30, 33 ] ], "normalized": [] }, { "id": "PMC-2791889-15-Experimental_Procedures-06_T2", "type": "Protein", "text": [ "ERK" ], "offsets": [ [ 256, 259 ] ], "normalized": [] }, { "id": "PMC-2791889-15-Experimental_Procedures-06_T3", "type": "Protein", "text": [ "actin" ], "offsets": [ [ 264, 269 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-10022882__text", "type": "abstract", "text": [ "Reactive oxygen intermediate-dependent NF-kappaB activation by interleukin-1beta requires 5-lipoxygenase or NADPH oxidase activity. \nWe previously reported that the role of reactive oxygen intermediates (ROIs) in NF-kappaB activation by proinflammatory cytokines was cell specific. However, the sources for ROIs in various cell types are yet to be determined and might include 5-lipoxygenase (5-LOX) and NADPH oxidase. 5-LOX and 5-LOX activating protein (FLAP) are coexpressed in lymphoid cells but not in monocytic or epithelial cells. Stimulation of lymphoid cells with interleukin-1beta (IL-1beta) led to ROI production and NF-kappaB activation, which could both be blocked by antioxidants or FLAP inhibitors, confirming that 5-LOX was the source of ROIs and was required for NF-kappaB activation in these cells. IL-1beta stimulation of epithelial cells did not generate any ROIs and NF-kappaB induction was not influenced by 5-LOX inhibitors. However, reintroduction of a functional 5-LOX system in these cells allowed ROI production and 5-LOX-dependent NF-kappaB activation. In monocytic cells, IL-1beta treatment led to a production of ROIs which is independent of the 5-LOX enzyme but requires the NADPH oxidase activity. This pathway involves the Rac1 and Cdc42 GTPases, two enzymes which are not required for NF-kappaB activation by IL-1beta in epithelial cells. In conclusion, three different cell-specific pathways lead to NF-kappaB activation by IL-1beta: a pathway dependent on ROI production by 5-LOX in lymphoid cells, an ROI- and 5-LOX-independent pathway in epithelial cells, and a pathway requiring ROI production by NADPH oxidase in monocytic cells. " ], "offsets": [ [ 0, 1669 ] ] } ]

[ { "id": "PMID-10022882_T1", "type": "Protein", "text": [ "interleukin-1beta" ], "offsets": [ [ 63, 80 ] ], "normalized": [] }, { "id": "PMID-10022882_T2", "type": "Protein", "text": [ "5-lipoxygenase" ], "offsets": [ [ 90, 104 ] ], "normalized": [] }, { "id": "PMID-10022882_T3", "type": "Protein", "text": [ "5-lipoxygenase" ], "offsets": [ [ 377, 391 ] ], "normalized": [] }, { "id": "PMID-10022882_T4", "type": "Protein", "text": [ "5-LOX" ], "offsets": [ [ 393, 398 ] ], "normalized": [] }, { "id": "PMID-10022882_T5", "type": "Protein", "text": [ "5-LOX" ], "offsets": [ [ 419, 424 ] ], "normalized": [] }, { "id": "PMID-10022882_T6", "type": "Protein", "text": [ "5-LOX" ], "offsets": [ [ 429, 434 ] ], "normalized": [] }, { "id": "PMID-10022882_T7", "type": "Protein", "text": [ "FLAP" ], "offsets": [ [ 455, 459 ] ], "normalized": [] }, { "id": "PMID-10022882_T8", "type": "Protein", "text": [ "interleukin-1beta" ], "offsets": [ [ 572, 589 ] ], "normalized": [] }, { "id": "PMID-10022882_T9", "type": "Protein", "text": [ "IL-1beta" ], "offsets": [ [ 591, 599 ] ], "normalized": [] }, { "id": "PMID-10022882_T10", "type": "Protein", "text": [ "FLAP" ], "offsets": [ [ 696, 700 ] ], "normalized": [] }, { "id": "PMID-10022882_T11", "type": "Protein", "text": [ "5-LOX" ], "offsets": [ [ 729, 734 ] ], "normalized": [] }, { "id": "PMID-10022882_T12", "type": "Protein", "text": [ "IL-1beta" ], "offsets": [ [ 816, 824 ] ], "normalized": [] }, { "id": "PMID-10022882_T13", "type": "Protein", "text": [ "5-LOX" ], "offsets": [ [ 929, 934 ] ], "normalized": [] }, { "id": "PMID-10022882_T14", "type": "Protein", "text": [ "5-LOX" ], "offsets": [ [ 987, 992 ] ], "normalized": [] }, { "id": "PMID-10022882_T15", "type": "Protein", "text": [ "5-LOX" ], "offsets": [ [ 1042, 1047 ] ], "normalized": [] }, { "id": "PMID-10022882_T16", "type": "Protein", "text": [ "IL-1beta" ], "offsets": [ [ 1100, 1108 ] ], "normalized": [] }, { "id": "PMID-10022882_T17", "type": "Protein", "text": [ "5-LOX" ], "offsets": [ [ 1175, 1180 ] ], "normalized": [] }, { "id": "PMID-10022882_T18", "type": "Protein", "text": [ "Rac1" ], "offsets": [ [ 1255, 1259 ] ], "normalized": [] }, { "id": "PMID-10022882_T19", "type": "Protein", "text": [ "Cdc42" ], "offsets": [ [ 1264, 1269 ] ], "normalized": [] }, { "id": "PMID-10022882_T20", "type": "Protein", "text": [ "IL-1beta" ], "offsets": [ [ 1342, 1350 ] ], "normalized": [] }, { "id": "PMID-10022882_T21", "type": "Protein", "text": [ "IL-1beta" ], "offsets": [ [ 1458, 1466 ] ], "normalized": [] }, { "id": "PMID-10022882_T22", "type": "Protein", "text": [ "5-LOX" ], "offsets": [ [ 1509, 1514 ] ], "normalized": [] }, { "id": "PMID-10022882_T23", "type": "Protein", "text": [ "5-LOX" ], "offsets": [ [ 1546, 1551 ] ], "normalized": [] } ]

[ { "id": "PMID-10022882_E1", "type": "Gene_expression", "trigger": { "text": [ "coexpressed" ], "offsets": [ [ 465, 476 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022882_T5" } ] }, { "id": "PMID-10022882_E2", "type": "Gene_expression", "trigger": { "text": [ "coexpressed" ], "offsets": [ [ 465, 476 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022882_T7" } ] } ]

[ { "id": "PMID-10022882_1", "entity_ids": [ "PMID-10022882_T8", "PMID-10022882_T9" ] }, { "id": "PMID-10022882_2", "entity_ids": [ "PMID-10022882_T3", "PMID-10022882_T4" ] } ]

[]

[ { "id": "PMID-10022897__text", "type": "abstract", "text": [ "Activation-dependent transcriptional regulation of the human Fas promoter requires NF-kappaB p50-p65 recruitment. \nFas (CD95) and Fas ligand (CD95L) are an interacting receptor-ligand pair required for immune homeostasis. Lymphocyte activation results in the upregulation of Fas expression and the acquisition of sensitivity to FasL-mediated apoptosis. Although Fas upregulation is central to the preservation of immunologic tolerance, little is known about the molecular machinery underlying this process. To investigate the events involved in activation-induced Fas upregulation, we have examined mRNA accumulation, fas promoter activity, and protein expression in the Jurkat T-cell line treated with phorbol myristate acetate and ionomycin (P/I), pharmacological mimics of T-cell receptor activation. Although resting Jurkat cells express Fas, Fas mRNA was induced approximately 10-fold in 2 h upon P/I stimulation. Using sequential deletion mutants of the human fas promoter in transient transfection assays, we identified a 47-bp sequence (positions -306 to -260 relative to the ATG) required for activation-driven fas upregulation. Sequence analysis revealed the presence of a previously unrecognized composite binding site for both the Sp1 and NF-kappaB transcription factors at positions -295 to -286. Electrophoretic mobility shift assay (EMSA) and supershift analyses of this region documented constitutive binding of Sp1 in unactivated nuclear extracts and inducible binding of p50-p65 NF-kappaB heterodimers after P/I activation. Sp1 and NF-kappaB transcription factor binding was shown to be mutually exclusive by EMSA displacement studies with purified recombinant Sp1 and recombinant p50. The functional contribution of the kappaB-Sp1 composite site in P/I-inducible fas promoter activation was verified by using kappaB-Sp1 concatamers (-295 to -286) in a thymidine kinase promoter-driven reporter construct and native promoter constructs in Jurkat cells overexpressing IkappaB-alpha. Site-directed mutagenesis of the critical guanine nucleotides in the kappaB-Sp1 element documented the essential role of this site in activation-dependent fas promoter induction. " ], "offsets": [ [ 0, 2179 ] ] } ]

[ { "id": "PMID-10022897_T1", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 61, 64 ] ], "normalized": [] }, { "id": "PMID-10022897_T2", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 93, 96 ] ], "normalized": [] }, { "id": "PMID-10022897_T3", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 97, 100 ] ], "normalized": [] }, { "id": "PMID-10022897_T4", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 115, 118 ] ], "normalized": [] }, { "id": "PMID-10022897_T5", "type": "Protein", "text": [ "CD95" ], "offsets": [ [ 120, 124 ] ], "normalized": [] }, { "id": "PMID-10022897_T6", "type": "Protein", "text": [ "Fas ligand" ], "offsets": [ [ 130, 140 ] ], "normalized": [] }, { "id": "PMID-10022897_T7", "type": "Protein", "text": [ "CD95L" ], "offsets": [ [ 142, 147 ] ], "normalized": [] }, { "id": "PMID-10022897_T8", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 275, 278 ] ], "normalized": [] }, { "id": "PMID-10022897_T9", "type": "Protein", "text": [ "FasL" ], "offsets": [ [ 328, 332 ] ], "normalized": [] }, { "id": "PMID-10022897_T10", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 362, 365 ] ], "normalized": [] }, { "id": "PMID-10022897_T11", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 564, 567 ] ], "normalized": [] }, { "id": "PMID-10022897_T12", "type": "Protein", "text": [ "fas" ], "offsets": [ [ 618, 621 ] ], "normalized": [] }, { "id": "PMID-10022897_T13", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 842, 845 ] ], "normalized": [] }, { "id": "PMID-10022897_T14", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 847, 850 ] ], "normalized": [] }, { "id": "PMID-10022897_T15", "type": "Protein", "text": [ "fas" ], "offsets": [ [ 966, 969 ] ], "normalized": [] }, { "id": "PMID-10022897_T16", "type": "Protein", "text": [ "fas" ], "offsets": [ [ 1120, 1123 ] ], "normalized": [] }, { "id": "PMID-10022897_T17", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 1243, 1246 ] ], "normalized": [] }, { "id": "PMID-10022897_T18", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 1428, 1431 ] ], "normalized": [] }, { "id": "PMID-10022897_T19", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1489, 1492 ] ], "normalized": [] }, { "id": "PMID-10022897_T20", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1493, 1496 ] ], "normalized": [] }, { "id": "PMID-10022897_T21", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 1542, 1545 ] ], "normalized": [] }, { "id": "PMID-10022897_T22", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 1679, 1682 ] ], "normalized": [] }, { "id": "PMID-10022897_T23", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1699, 1702 ] ], "normalized": [] }, { "id": "PMID-10022897_T24", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 1746, 1749 ] ], "normalized": [] }, { "id": "PMID-10022897_T25", "type": "Protein", "text": [ "fas" ], "offsets": [ [ 1782, 1785 ] ], "normalized": [] }, { "id": "PMID-10022897_T26", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 1835, 1838 ] ], "normalized": [] }, { "id": "PMID-10022897_T27", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1985, 1998 ] ], "normalized": [] }, { "id": "PMID-10022897_T28", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 2076, 2079 ] ], "normalized": [] }, { "id": "PMID-10022897_T29", "type": "Protein", "text": [ "fas" ], "offsets": [ [ 2155, 2158 ] ], "normalized": [] }, { "id": "PMID-10022897_T32", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 65, 73 ] ], "normalized": [] }, { "id": "PMID-10022897_T51", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1786, 1794 ] ], "normalized": [] }, { "id": "PMID-10022897_T54", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 2159, 2167 ] ], "normalized": [] } ]

[ { "id": "PMID-10022897_E1", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 11, 20 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_E2" } ] }, { "id": "PMID-10022897_E2", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 37, 47 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T1" }, { "role": "Site", "ref_id": "PMID-10022897_T32" } ] }, { "id": "PMID-10022897_E3", "type": "Positive_regulation", "trigger": { "text": [ "requires" ], "offsets": [ [ 74, 82 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_E2" }, { "role": "Cause", "ref_id": "PMID-10022897_E5" } ] }, { "id": "PMID-10022897_E4", "type": "Positive_regulation", "trigger": { "text": [ "requires" ], "offsets": [ [ 74, 82 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_E2" }, { "role": "Cause", "ref_id": "PMID-10022897_E6" } ] }, { "id": "PMID-10022897_E5", "type": "Positive_regulation", "trigger": { "text": [ "recruitment" ], "offsets": [ [ 101, 112 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T2" } ] }, { "id": "PMID-10022897_E6", "type": "Positive_regulation", "trigger": { "text": [ "recruitment" ], "offsets": [ [ 101, 112 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T3" } ] }, { "id": "PMID-10022897_E7", "type": "Binding", "trigger": { "text": [ "interacting receptor-ligand pair" ], "offsets": [ [ 156, 188 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T5" }, { "role": "Theme", "ref_id": "PMID-10022897_T7" } ] }, { "id": "PMID-10022897_E8", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 259, 271 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_E9" } ] }, { "id": "PMID-10022897_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 279, 289 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T8" } ] }, { "id": "PMID-10022897_E10", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 366, 378 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T10" } ] }, { "id": "PMID-10022897_E11", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 556, 563 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_E12" } ] }, { "id": "PMID-10022897_E12", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 568, 580 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T11" } ] }, { "id": "PMID-10022897_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 653, 663 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T11" } ] }, { "id": "PMID-10022897_E14", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 834, 841 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T13" } ] }, { "id": "PMID-10022897_E15", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 860, 867 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T14" } ] }, { "id": "PMID-10022897_E16", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 1089, 1097 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_E17" } ] }, { "id": "PMID-10022897_E17", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 1124, 1136 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T16" } ] }, { "id": "PMID-10022897_E18", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1417, 1424 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T18" } ] }, { "id": "PMID-10022897_E19", "type": "Positive_regulation", "trigger": { "text": [ "inducible" ], "offsets": [ [ 1468, 1477 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_E21" } ] }, { "id": "PMID-10022897_E20", "type": "Positive_regulation", "trigger": { "text": [ "inducible" ], "offsets": [ [ 1468, 1477 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_E22" } ] }, { "id": "PMID-10022897_E21", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1478, 1485 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T20" } ] }, { "id": "PMID-10022897_E22", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1478, 1485 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T19" } ] }, { "id": "PMID-10022897_E23", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1581, 1588 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T21" } ] }, { "id": "PMID-10022897_E24", "type": "Negative_regulation", "trigger": { "text": [ "mutually exclusive" ], "offsets": [ [ 1605, 1623 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_E23" } ] }, { "id": "PMID-10022897_E25", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1795, 1805 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T25" }, { "role": "Site", "ref_id": "PMID-10022897_T51" } ] }, { "id": "PMID-10022897_E26", "type": "Positive_regulation", "trigger": { "text": [ "essential role" ], "offsets": [ [ 2103, 2117 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_E27" } ] }, { "id": "PMID-10022897_E27", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 2168, 2177 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10022897_T29" }, { "role": "Site", "ref_id": "PMID-10022897_T54" } ] } ]

[ { "id": "PMID-10022897_1", "entity_ids": [ "PMID-10022897_T7", "PMID-10022897_T6" ] }, { "id": "PMID-10022897_2", "entity_ids": [ "PMID-10022897_T5", "PMID-10022897_T4" ] } ]

[]

[ { "id": "PMID-10023774__text", "type": "abstract", "text": [ "RFLAT-1: a new zinc finger transcription factor that activates RANTES gene expression in T lymphocytes. \nRANTES (Regulated upon Activation, Normal T cell Expressed and Secreted) is a chemoattractant cytokine (chemokine) important in the generation of inflammatory infiltrate and human immunodeficiency virus entry into immune cells. RANTES is expressed late (3-5 days) after activation in T lymphocytes. Using expression cloning, we identified the first \"late\" T lymphocyte associated transcription factor and named it \"RANTES Factor of Late Activated T Lymphocytes-1\" (RFLAT-1). RFLAT-1 is a novel, phosphorylated, zinc finger transcription factor that is expressed in T cells 3 days after activation, coincident with RANTES expression. While Rel proteins play the dominant role in RANTES gene expression in fibroblasts, RFLAT-1 is a strong transactivator for RANTES in T cells. " ], "offsets": [ [ 0, 880 ] ] } ]

[ { "id": "PMID-10023774_T1", "type": "Protein", "text": [ "RFLAT-1" ], "offsets": [ [ 0, 7 ] ], "normalized": [] }, { "id": "PMID-10023774_T2", "type": "Protein", "text": [ "RANTES" ], "offsets": [ [ 63, 69 ] ], "normalized": [] }, { "id": "PMID-10023774_T3", "type": "Protein", "text": [ "RANTES" ], "offsets": [ [ 105, 111 ] ], "normalized": [] }, { "id": "PMID-10023774_T4", "type": "Protein", "text": [ "Regulated upon Activation, Normal T cell Expressed and Secreted" ], "offsets": [ [ 113, 176 ] ], "normalized": [] }, { "id": "PMID-10023774_T5", "type": "Protein", "text": [ "RANTES" ], "offsets": [ [ 333, 339 ] ], "normalized": [] }, { "id": "PMID-10023774_T6", "type": "Protein", "text": [ "RANTES Factor of Late Activated T Lymphocytes-1" ], "offsets": [ [ 520, 567 ] ], "normalized": [] }, { "id": "PMID-10023774_T7", "type": "Protein", "text": [ "RFLAT-1" ], "offsets": [ [ 570, 577 ] ], "normalized": [] }, { "id": "PMID-10023774_T8", "type": "Protein", "text": [ "RFLAT-1" ], "offsets": [ [ 580, 587 ] ], "normalized": [] }, { "id": "PMID-10023774_T9", "type": "Protein", "text": [ "RANTES" ], "offsets": [ [ 719, 725 ] ], "normalized": [] }, { "id": "PMID-10023774_T10", "type": "Protein", "text": [ "RANTES" ], "offsets": [ [ 783, 789 ] ], "normalized": [] }, { "id": "PMID-10023774_T11", "type": "Protein", "text": [ "RFLAT-1" ], "offsets": [ [ 822, 829 ] ], "normalized": [] }, { "id": "PMID-10023774_T12", "type": "Protein", "text": [ "RANTES" ], "offsets": [ [ 861, 867 ] ], "normalized": [] } ]

[ { "id": "PMID-10023774_E1", "type": "Positive_regulation", "trigger": { "text": [ "activates" ], "offsets": [ [ 53, 62 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10023774_E2" }, { "role": "Cause", "ref_id": "PMID-10023774_T1" } ] }, { "id": "PMID-10023774_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 75, 85 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10023774_T2" } ] }, { "id": "PMID-10023774_E3", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 343, 352 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10023774_T5" } ] }, { "id": "PMID-10023774_E4", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 600, 614 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10023774_T8" } ] }, { "id": "PMID-10023774_E5", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 657, 666 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10023774_T8" } ] }, { "id": "PMID-10023774_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 726, 736 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10023774_T9" } ] }, { "id": "PMID-10023774_E7", "type": "Positive_regulation", "trigger": { "text": [ "dominant role" ], "offsets": [ [ 766, 779 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10023774_E8" } ] }, { "id": "PMID-10023774_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 795, 805 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10023774_T10" } ] }, { "id": "PMID-10023774_E9", "type": "Positive_regulation", "trigger": { "text": [ "transactivator" ], "offsets": [ [ 842, 856 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10023774_T12" }, { "role": "Cause", "ref_id": "PMID-10023774_T11" } ] } ]

[ { "id": "PMID-10023774_1", "entity_ids": [ "PMID-10023774_T3", "PMID-10023774_T4" ] } ]

[]

[ { "id": "PMID-10029571__text", "type": "abstract", "text": [ "Interleukin-10 inhibits expression of both interferon alpha- and interferon gamma- induced genes by suppressing tyrosine phosphorylation of STAT1. \nInterleukin-10 (IL-10) helps maintain polarized T-helper cells in a T-helper lymphocyte 2 (Th2) phenotype. Part of this process involves the prevention of the development of Th1 cells, which are a primary source of interferon gamma (IFNgamma), a potent activator of monocytes and an inhibitor of Th2 proliferation. Because monocytes and macrophages are important mediators of Th1-type responses, such as delayed-type hypersensitivity, we sought to determine if IL-10 could directly mediate inhibition of IFNgamma- and IFNalpha-induced gene expression in these cells. Highly purified monocytes were incubated with IL-10 for 60 to 90 minutes before the addition of IFNgamma or IFNalpha. IL-10 preincubation resulted in the inhibition of gene expression for several IFN-induced genes, such as IP-10, ISG54, and intercellular adhesion molecule-1. The reduction in gene expression resulted from the ability of IL-10 to suppress IFN-induced assembly of signal transducer and activator of transcription (STAT) factors to specific promoter motifs on IFNalpha- and IFNgamma-inducible genes. This was accomplished by preventing the IFN-induced tyrosine phosphorylation of STAT1, a component of both IFNalpha- and IFNgamma-induced DNA binding complexes. Therefore, IL-10 can directly inhibit STAT-dependent early response gene expression induced by both IFNalpha and IFNgamma in monocytes by suppressing the tyrosine phosphorylation of STAT1. This may occur through the ability of IL-10 to induce expression of the gene, suppressor of cytokine signaling 3 (SOCS3). " ], "offsets": [ [ 0, 1702 ] ] } ]

[ { "id": "PMID-10029571_T1", "type": "Protein", "text": [ "Interleukin-10" ], "offsets": [ [ 0, 14 ] ], "normalized": [] }, { "id": "PMID-10029571_T2", "type": "Protein", "text": [ "interferon gamma" ], "offsets": [ [ 65, 81 ] ], "normalized": [] }, { "id": "PMID-10029571_T3", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 140, 145 ] ], "normalized": [] }, { "id": "PMID-10029571_T4", "type": "Protein", "text": [ "Interleukin-10" ], "offsets": [ [ 148, 162 ] ], "normalized": [] }, { "id": "PMID-10029571_T5", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 164, 169 ] ], "normalized": [] }, { "id": "PMID-10029571_T6", "type": "Protein", "text": [ "interferon gamma" ], "offsets": [ [ 363, 379 ] ], "normalized": [] }, { "id": "PMID-10029571_T7", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 381, 389 ] ], "normalized": [] }, { "id": "PMID-10029571_T8", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 609, 614 ] ], "normalized": [] }, { "id": "PMID-10029571_T9", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 652, 660 ] ], "normalized": [] }, { "id": "PMID-10029571_T10", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 761, 766 ] ], "normalized": [] }, { "id": "PMID-10029571_T11", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 811, 819 ] ], "normalized": [] }, { "id": "PMID-10029571_T12", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 833, 838 ] ], "normalized": [] }, { "id": "PMID-10029571_T13", "type": "Protein", "text": [ "IP-10" ], "offsets": [ [ 938, 943 ] ], "normalized": [] }, { "id": "PMID-10029571_T14", "type": "Protein", "text": [ "ISG54" ], "offsets": [ [ 945, 950 ] ], "normalized": [] }, { "id": "PMID-10029571_T15", "type": "Protein", "text": [ "intercellular adhesion molecule-1" ], "offsets": [ [ 956, 989 ] ], "normalized": [] }, { "id": "PMID-10029571_T16", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1053, 1058 ] ], "normalized": [] }, { "id": "PMID-10029571_T17", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1204, 1212 ] ], "normalized": [] }, { "id": "PMID-10029571_T18", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 1310, 1315 ] ], "normalized": [] }, { "id": "PMID-10029571_T19", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1351, 1359 ] ], "normalized": [] }, { "id": "PMID-10029571_T20", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1402, 1407 ] ], "normalized": [] }, { "id": "PMID-10029571_T21", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1504, 1512 ] ], "normalized": [] }, { "id": "PMID-10029571_T22", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 1573, 1578 ] ], "normalized": [] }, { "id": "PMID-10029571_T23", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1618, 1623 ] ], "normalized": [] }, { "id": "PMID-10029571_T24", "type": "Protein", "text": [ "suppressor of cytokine signaling 3" ], "offsets": [ [ 1658, 1692 ] ], "normalized": [] }, { "id": "PMID-10029571_T25", "type": "Protein", "text": [ "SOCS3" ], "offsets": [ [ 1694, 1699 ] ], "normalized": [] }, { "id": "PMID-10029571_T27", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 112, 120 ] ], "normalized": [] }, { "id": "PMID-10029571_T37", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 1282, 1290 ] ], "normalized": [] }, { "id": "PMID-10029571_T41", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 1545, 1553 ] ], "normalized": [] } ]

[ { "id": "PMID-10029571_E1", "type": "Negative_regulation", "trigger": { "text": [ "suppressing" ], "offsets": [ [ 100, 111 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_E2" }, { "role": "Cause", "ref_id": "PMID-10029571_T1" } ] }, { "id": "PMID-10029571_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 121, 136 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_T3" }, { "role": "Site", "ref_id": "PMID-10029571_T27" } ] }, { "id": "PMID-10029571_E3", "type": "Gene_expression", "trigger": { "text": [ "primary source" ], "offsets": [ [ 345, 359 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_T7" } ] }, { "id": "PMID-10029571_E4", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 869, 879 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_E7" } ] }, { "id": "PMID-10029571_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 869, 879 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_E9" } ] }, { "id": "PMID-10029571_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 869, 879 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_E8" } ] }, { "id": "PMID-10029571_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 888, 898 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_T15" } ] }, { "id": "PMID-10029571_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 888, 898 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_T14" } ] }, { "id": "PMID-10029571_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 888, 898 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_T13" } ] }, { "id": "PMID-10029571_E10", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 915, 922 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_T15" } ] }, { "id": "PMID-10029571_E11", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 915, 922 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_T14" } ] }, { "id": "PMID-10029571_E12", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 915, 922 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_T13" } ] }, { "id": "PMID-10029571_E13", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 1024, 1032 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_E6" } ] }, { "id": "PMID-10029571_E14", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 1024, 1032 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_E5" } ] }, { "id": "PMID-10029571_E15", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 1024, 1032 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_E4" } ] }, { "id": "PMID-10029571_E16", "type": "Positive_regulation", "trigger": { "text": [ "accomplished" ], "offsets": [ [ 1239, 1251 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_E13" }, { "role": "Cause", "ref_id": "PMID-10029571_E19" } ] }, { "id": "PMID-10029571_E17", "type": "Positive_regulation", "trigger": { "text": [ "accomplished" ], "offsets": [ [ 1239, 1251 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_E15" }, { "role": "Cause", "ref_id": "PMID-10029571_E19" } ] }, { "id": "PMID-10029571_E18", "type": "Positive_regulation", "trigger": { "text": [ "accomplished" ], "offsets": [ [ 1239, 1251 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_E14" }, { "role": "Cause", "ref_id": "PMID-10029571_E19" } ] }, { "id": "PMID-10029571_E19", "type": "Negative_regulation", "trigger": { "text": [ "preventing" ], "offsets": [ [ 1255, 1265 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_E20" } ] }, { "id": "PMID-10029571_E20", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1274, 1281 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_E21" } ] }, { "id": "PMID-10029571_E21", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1291, 1306 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_T18" }, { "role": "Site", "ref_id": "PMID-10029571_T37" } ] }, { "id": "PMID-10029571_E22", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1360, 1367 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_T18" } ] }, { "id": "PMID-10029571_E23", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1360, 1367 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_T18" }, { "role": "Cause", "ref_id": "PMID-10029571_T19" } ] }, { "id": "PMID-10029571_E24", "type": "Negative_regulation", "trigger": { "text": [ "suppressing" ], "offsets": [ [ 1529, 1540 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_E25" }, { "role": "Cause", "ref_id": "PMID-10029571_T20" } ] }, { "id": "PMID-10029571_E25", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1554, 1569 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_T22" }, { "role": "Site", "ref_id": "PMID-10029571_T41" } ] }, { "id": "PMID-10029571_E26", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 1627, 1633 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_E27" }, { "role": "Cause", "ref_id": "PMID-10029571_T23" } ] }, { "id": "PMID-10029571_E27", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1634, 1644 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029571_T25" } ] } ]

[ { "id": "PMID-10029571_1", "entity_ids": [ "PMID-10029571_T25", "PMID-10029571_T24" ] }, { "id": "PMID-10029571_2", "entity_ids": [ "PMID-10029571_T7", "PMID-10029571_T6" ] }, { "id": "PMID-10029571_3", "entity_ids": [ "PMID-10029571_T4", "PMID-10029571_T5" ] } ]

[]

[ { "id": "PMID-10029589__text", "type": "abstract", "text": [ "The Megakaryocyte/Platelet-specific enhancer of the alpha2beta1 integrin gene: two tandem AP1 sites and the mitogen-activated protein kinase signaling cascade. \nThe alpha2beta1 integrin, a collagen receptor on platelets and megakaryocytes, is required for normal platelet function. Transcriptional regulation of the alpha2 integrin gene in cells undergoing megakaryocytic differentiation requires a core promoter between bp -30 and -92, a silencer between bp -92 and -351, and megakaryocytic enhancers in the distal 5' flank. We have now identified a 229-bp region of the distal 5' flank of the alpha2 integrin gene required for high-level enhancer activity in cells with megakaryocytic features. Two tandem AP1 binding sites with dyad symmetry are required for enhancer activity and for DNA-protein complex formation with members of the c-fos/c-jun family. The requirement for AP1 activation suggested a role for the mitogen-activated protein kinase (MAPK) signaling pathway in regulating alpha2 integrin gene expression. Inhibition of the MAP kinase cascade with PD98059, a specific inhibitor of MAPK kinase 1, prevented the expression of the alpha2 integrin subunit in cells induced to become megakaryocytic. We provide a model of megakaryocytic differentiation in which expression of the alpha2 integrin gene requires signaling via the MAP kinase pathway to activate two tandem AP1 binding sites in the alpha2 integrin enhancer. " ], "offsets": [ [ 0, 1433 ] ] } ]

[ { "id": "PMID-10029589_T1", "type": "Protein", "text": [ "alpha2 integrin" ], "offsets": [ [ 316, 331 ] ], "normalized": [] }, { "id": "PMID-10029589_T2", "type": "Protein", "text": [ "alpha2 integrin" ], "offsets": [ [ 595, 610 ] ], "normalized": [] }, { "id": "PMID-10029589_T3", "type": "Protein", "text": [ "c-fos" ], "offsets": [ [ 838, 843 ] ], "normalized": [] }, { "id": "PMID-10029589_T4", "type": "Protein", "text": [ "c-jun" ], "offsets": [ [ 844, 849 ] ], "normalized": [] }, { "id": "PMID-10029589_T5", "type": "Protein", "text": [ "alpha2 integrin" ], "offsets": [ [ 990, 1005 ] ], "normalized": [] }, { "id": "PMID-10029589_T6", "type": "Protein", "text": [ "MAPK kinase 1" ], "offsets": [ [ 1098, 1111 ] ], "normalized": [] }, { "id": "PMID-10029589_T7", "type": "Protein", "text": [ "alpha2 integrin" ], "offsets": [ [ 1145, 1160 ] ], "normalized": [] }, { "id": "PMID-10029589_T8", "type": "Protein", "text": [ "alpha2 integrin" ], "offsets": [ [ 1292, 1307 ] ], "normalized": [] }, { "id": "PMID-10029589_T9", "type": "Protein", "text": [ "alpha2 integrin" ], "offsets": [ [ 1407, 1422 ] ], "normalized": [] } ]

[ { "id": "PMID-10029589_E1", "type": "Regulation", "trigger": { "text": [ "Transcriptional regulation" ], "offsets": [ [ 282, 308 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029589_T1" } ] }, { "id": "PMID-10029589_E2", "type": "Positive_regulation", "trigger": { "text": [ "requires" ], "offsets": [ [ 388, 396 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029589_E1" } ] }, { "id": "PMID-10029589_E3", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 749, 757 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029589_E6" } ] }, { "id": "PMID-10029589_E4", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 749, 757 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029589_E5" } ] }, { "id": "PMID-10029589_E5", "type": "Binding", "trigger": { "text": [ "complex formation" ], "offsets": [ [ 800, 817 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029589_T3" } ] }, { "id": "PMID-10029589_E6", "type": "Binding", "trigger": { "text": [ "complex formation" ], "offsets": [ [ 800, 817 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029589_T4" } ] }, { "id": "PMID-10029589_E7", "type": "Positive_regulation", "trigger": { "text": [ "requirement" ], "offsets": [ [ 862, 873 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029589_E9" } ] }, { "id": "PMID-10029589_E8", "type": "Positive_regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 905, 909 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029589_E9" } ] }, { "id": "PMID-10029589_E9", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 979, 989 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029589_E10" } ] }, { "id": "PMID-10029589_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1011, 1021 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029589_T5" } ] }, { "id": "PMID-10029589_E11", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 1085, 1094 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029589_T6" } ] }, { "id": "PMID-10029589_E12", "type": "Negative_regulation", "trigger": { "text": [ "prevented" ], "offsets": [ [ 1113, 1122 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029589_E13" } ] }, { "id": "PMID-10029589_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1127, 1137 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029589_T7" } ] }, { "id": "PMID-10029589_E14", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1274, 1284 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029589_T8" } ] }, { "id": "PMID-10029589_E15", "type": "Positive_regulation", "trigger": { "text": [ "requires" ], "offsets": [ [ 1313, 1321 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10029589_E14" } ] } ]

[]

[]

[ { "id": "PMID-10037138__text", "type": "abstract", "text": [ "Differential expression and phosphorylation of CTCF, a c-myc transcriptional regulator, during differentiation of human myeloid cells. \nCTCF is a transcriptional repressor of the c-myc gene. Although CTCF has been characterized in some detail, there is very little information about the regulation of CTCF activity. Therefore we investigated CTCF expression and phosphorylation during induced differentiation of human myeloid leukemia cells. We found that: (i) both CTCF mRNA and protein are down-regulated during terminal differentiation in most cell lines tested; (ii) CTCF down-regulation is retarded and less pronounced than that of c-myc; (iii) CTCF protein is differentially phosphorylated and the phosphorylation profiles depend on the differentiation pathway. We concluded that CTCF expression and activity is controlled at transcriptional and post-transcriptional levels. " ], "offsets": [ [ 0, 881 ] ] } ]

[ { "id": "PMID-10037138_T1", "type": "Protein", "text": [ "CTCF" ], "offsets": [ [ 47, 51 ] ], "normalized": [] }, { "id": "PMID-10037138_T2", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 55, 60 ] ], "normalized": [] }, { "id": "PMID-10037138_T3", "type": "Protein", "text": [ "CTCF" ], "offsets": [ [ 136, 140 ] ], "normalized": [] }, { "id": "PMID-10037138_T4", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 179, 184 ] ], "normalized": [] }, { "id": "PMID-10037138_T5", "type": "Protein", "text": [ "CTCF" ], "offsets": [ [ 200, 204 ] ], "normalized": [] }, { "id": "PMID-10037138_T6", "type": "Protein", "text": [ "CTCF" ], "offsets": [ [ 301, 305 ] ], "normalized": [] }, { "id": "PMID-10037138_T7", "type": "Protein", "text": [ "CTCF" ], "offsets": [ [ 342, 346 ] ], "normalized": [] }, { "id": "PMID-10037138_T8", "type": "Protein", "text": [ "CTCF" ], "offsets": [ [ 466, 470 ] ], "normalized": [] }, { "id": "PMID-10037138_T9", "type": "Protein", "text": [ "CTCF" ], "offsets": [ [ 571, 575 ] ], "normalized": [] }, { "id": "PMID-10037138_T10", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 637, 642 ] ], "normalized": [] }, { "id": "PMID-10037138_T11", "type": "Protein", "text": [ "CTCF" ], "offsets": [ [ 650, 654 ] ], "normalized": [] }, { "id": "PMID-10037138_T12", "type": "Protein", "text": [ "CTCF" ], "offsets": [ [ 786, 790 ] ], "normalized": [] } ]

[ { "id": "PMID-10037138_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 13, 23 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037138_T1" } ] }, { "id": "PMID-10037138_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 28, 43 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037138_T1" } ] }, { "id": "PMID-10037138_E3", "type": "Regulation", "trigger": { "text": [ "transcriptional regulator" ], "offsets": [ [ 61, 86 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037138_T2" }, { "role": "Cause", "ref_id": "PMID-10037138_T1" } ] }, { "id": "PMID-10037138_E4", "type": "Negative_regulation", "trigger": { "text": [ "transcriptional repressor" ], "offsets": [ [ 146, 171 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037138_T4" }, { "role": "Cause", "ref_id": "PMID-10037138_T3" } ] }, { "id": "PMID-10037138_E5", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 287, 297 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037138_T6" } ] }, { "id": "PMID-10037138_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 347, 357 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037138_T7" } ] }, { "id": "PMID-10037138_E7", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 362, 377 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037138_T7" } ] }, { "id": "PMID-10037138_E8", "type": "Negative_regulation", "trigger": { "text": [ "down-regulated" ], "offsets": [ [ 492, 506 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037138_T8" } ] }, { "id": "PMID-10037138_E9", "type": "Negative_regulation", "trigger": { "text": [ "down-regulation" ], "offsets": [ [ 576, 591 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037138_T9" } ] }, { "id": "PMID-10037138_E10", "type": "Negative_regulation", "trigger": { "text": [ "down-regulation" ], "offsets": [ [ 576, 591 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037138_T10" } ] }, { "id": "PMID-10037138_E11", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 681, 695 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037138_T11" } ] }, { "id": "PMID-10037138_E12", "type": "Positive_regulation", "trigger": { "text": [ "depend" ], "offsets": [ [ 729, 735 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037138_E11" } ] }, { "id": "PMID-10037138_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 791, 801 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037138_T12" } ] }, { "id": "PMID-10037138_E14", "type": "Regulation", "trigger": { "text": [ "controlled at transcriptional and post-transcriptional levels" ], "offsets": [ [ 818, 879 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037138_E13" } ] }, { "id": "PMID-10037138_E15", "type": "Regulation", "trigger": { "text": [ "controlled at transcriptional and post-transcriptional levels" ], "offsets": [ [ 818, 879 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037138_T12" } ] } ]

[]

[]

[ { "id": "PMID-10037751__text", "type": "abstract", "text": [ "T-cell expression of the human GATA-3 gene is regulated by a non-lineage-specific silencer. \nThe GATA-3 transcription factor is required for development of the T-cell lineage and Th2 cytokine gene expression in CD4 T-cells. We have mapped the DNase-I-hypersensitive (HS) regions of the human GATA-3 gene in T-cells and non-T-cells and studied their transcriptional activities. HS I-III, located 5' from the transcriptional initiation site, were found in hematopoietic and non-hematopoietic cells, whereas HS IV-VII, located 3' from the transcriptional start site, were exclusively observed in T-cells. Among these hypersensitive sites, two transcriptional control elements were found, one in the first intron of the GATA-3 gene and the other between 8.3 and 5.9 kilobases 5' from the GATA-3 transcriptional initiation site. The first intron acted as a strong transcriptional activator in a position-dependent manner and with no cell-type specificity. The upstream regulatory element could confer T-cell specificity to the GATA-3 promoter activity, and analysis of this region revealed a 707-base pair silencer that drastically inhibited GATA-3 promoter activity in non-T-cells. Two CAGGTG E-boxes, located at the 5'- and 3'-ends of the silencer, were necessary for this silencer activity. The 3'-CAGGTG E-box could bind USF proteins, the ubiquitous repressor ZEB, or the basic helix-loop-helix proteins E2A and HEB, and we showed that a competition between ZEB and E2A/HEB proteins is involved in the silencer activity. " ], "offsets": [ [ 0, 1520 ] ] } ]

[ { "id": "PMID-10037751_T1", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 31, 37 ] ], "normalized": [] }, { "id": "PMID-10037751_T2", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 97, 103 ] ], "normalized": [] }, { "id": "PMID-10037751_T3", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 211, 214 ] ], "normalized": [] }, { "id": "PMID-10037751_T4", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 292, 298 ] ], "normalized": [] }, { "id": "PMID-10037751_T5", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 716, 722 ] ], "normalized": [] }, { "id": "PMID-10037751_T6", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 784, 790 ] ], "normalized": [] }, { "id": "PMID-10037751_T7", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 1022, 1028 ] ], "normalized": [] }, { "id": "PMID-10037751_T8", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 1137, 1143 ] ], "normalized": [] }, { "id": "PMID-10037751_T9", "type": "Protein", "text": [ "ZEB" ], "offsets": [ [ 1359, 1362 ] ], "normalized": [] }, { "id": "PMID-10037751_T10", "type": "Protein", "text": [ "E2A" ], "offsets": [ [ 1403, 1406 ] ], "normalized": [] }, { "id": "PMID-10037751_T11", "type": "Protein", "text": [ "HEB" ], "offsets": [ [ 1411, 1414 ] ], "normalized": [] }, { "id": "PMID-10037751_T12", "type": "Protein", "text": [ "ZEB" ], "offsets": [ [ 1457, 1460 ] ], "normalized": [] }, { "id": "PMID-10037751_T13", "type": "Protein", "text": [ "E2A" ], "offsets": [ [ 1465, 1468 ] ], "normalized": [] }, { "id": "PMID-10037751_T14", "type": "Protein", "text": [ "HEB" ], "offsets": [ [ 1469, 1472 ] ], "normalized": [] }, { "id": "PMID-10037751_T19", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1029, 1037 ] ], "normalized": [] }, { "id": "PMID-10037751_T21", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1144, 1152 ] ], "normalized": [] } ]

[ { "id": "PMID-10037751_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 7, 17 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037751_T1" } ] }, { "id": "PMID-10037751_E2", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 46, 55 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037751_E1" } ] }, { "id": "PMID-10037751_E3", "type": "Transcription", "trigger": { "text": [ "transcriptional" ], "offsets": [ [ 349, 364 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037751_T4" } ] }, { "id": "PMID-10037751_E4", "type": "Positive_regulation", "trigger": { "text": [ "confer" ], "offsets": [ [ 989, 995 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037751_T7" }, { "role": "Site", "ref_id": "PMID-10037751_T19" } ] }, { "id": "PMID-10037751_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1127, 1136 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037751_T8" }, { "role": "Site", "ref_id": "PMID-10037751_T21" } ] }, { "id": "PMID-10037751_E6", "type": "Positive_regulation", "trigger": { "text": [ "necessary" ], "offsets": [ [ 1251, 1260 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037751_E5" } ] }, { "id": "PMID-10037751_E7", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 1315, 1319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037751_T10" } ] }, { "id": "PMID-10037751_E8", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 1315, 1319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037751_T11" } ] }, { "id": "PMID-10037751_E9", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 1315, 1319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037751_T9" } ] }, { "id": "PMID-10037751_E10", "type": "Negative_regulation", "trigger": { "text": [ "competition" ], "offsets": [ [ 1437, 1448 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037751_E8" }, { "role": "Cause", "ref_id": "PMID-10037751_T12" } ] }, { "id": "PMID-10037751_E11", "type": "Negative_regulation", "trigger": { "text": [ "competition" ], "offsets": [ [ 1437, 1448 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037751_E7" }, { "role": "Cause", "ref_id": "PMID-10037751_T12" } ] }, { "id": "PMID-10037751_E12", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 1485, 1493 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037751_E5" }, { "role": "Cause", "ref_id": "PMID-10037751_E10" } ] }, { "id": "PMID-10037751_E13", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 1485, 1493 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10037751_E5" }, { "role": "Cause", "ref_id": "PMID-10037751_E11" } ] } ]

[]

[]

[ { "id": "PMID-10064064__text", "type": "abstract", "text": [ "AML and Ets proteins regulate the I alpha1 germ-line promoter. \nThe immunoglobulin heavy chain (IgH) class switch recombination of B lymphocytes preferentially targets unrearranged IgH genes that have already been rendered transcriptionally active. Transcription of the germ-line IgH genes is controlled by intervening (I) regions upstream of their switch regions. The I alpha1 promoter activates transcription of the human germ-line C alpha1 gene for IgA1 and mediates the transforming growth factor (TGF)-beta1 responsiveness of this locus. Here we show that the I alpha1 promoter contains several binding sites for the AML/PEBP2/CBF family of transcription factors and that AML and Ets proteins are major regulators of the basal and TGF-beta-inducible promoter activity. Our data constitute a starting point for studies to elucidate the molecular mechanism by which TGF-beta regulates IgA production. " ], "offsets": [ [ 0, 904 ] ] } ]

[ { "id": "PMID-10064064_T1", "type": "Protein", "text": [ "transforming growth factor (TGF)-beta1" ], "offsets": [ [ 474, 512 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-10064103__text", "type": "abstract", "text": [ "Peripheral blood mononuclear cells isolated from patients with diabetic nephropathy show increased activation of the oxidative-stress sensitive transcription factor NF-kappaB. \nIncreased oxidative stress and subsequent activation of the transcription factor NF-kappaB has been linked to the development of late diabetic complications. To determine whether oxidative stress dependent NF-kappaB activation is evident in patients with diabetic nephropathy we used an Electrophoretic Mobility Shift Assay based semiquantitative detection system which enabled us to determine NF-kappaB activation in ex vivo isolated peripheral blood mononuclear cells. We examined 33 patients with diabetes mellitus (Type I and Type II). Patients with diabetic nephropathy showed higher NF-kappaB binding activity in Electrophoretic Mobility Shift Assays and stronger immunohistological staining for activated NF-kappaBp65 than patients without renal complications. NF-kappaB binding activity correlated with the degree of albuminuria (r = 0.316) and with thrombomodulin plasma concentrations (r = 0.33), indicative for albuminuria associated endothelial dysfunction. In a 3 day intervention study in which 600 mg of the antioxidant thioctic acid (alpha-lipoic acid) per day were given to nine patients with diabetic nephropathy oxidative stress in plasma samples was decreased by 48% and NF-kappaB binding activity in ex vivo isolated peripheral blood mononuclear cells by 38%. In conclusion, activation of the transcription factor NF-kappaB in ex vivo isolated peripheral blood mononuclear cells of patients with diabetes mellitus correlates with the degree of diabetic nephropathy. NF-kappaB activation is at least in part dependent on oxidative stress since thioctic acid (alpha-lipoic acid) reduced NF-kappaB binding activity. " ], "offsets": [ [ 0, 1811 ] ] } ]

[ { "id": "PMID-10064103_T1", "type": "Protein", "text": [ "NF-kappaBp65" ], "offsets": [ [ 889, 901 ] ], "normalized": [] }, { "id": "PMID-10064103_T2", "type": "Protein", "text": [ "thrombomodulin" ], "offsets": [ [ 1035, 1049 ] ], "normalized": [] } ]

[ { "id": "PMID-10064103_E1", "type": "Positive_regulation", "trigger": { "text": [ "stronger" ], "offsets": [ [ 838, 846 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10064103_E2" } ] }, { "id": "PMID-10064103_E2", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 879, 888 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10064103_T1" } ] } ]

[]

[]

[ { "id": "PMID-10068588__text", "type": "abstract", "text": [ "Activation of human immunodeficiency virus type 1 expression by Gardnerella vaginalis. \nBacterial vaginosis (BV) is associated with an increased rate of sexual transmission of human immunodeficiency virus (HIV) type 1, and Gardnerella vaginalis is frequently isolated from the genital tracts of women with BV. G. vaginalis lysates were found to significantly stimulate HIV expression in monocytoid cells. Stimulation was significantly higher when lysates were heated at 100 degrees C for 5 min but was reduced by treatment with lysozyme or protease. G. vaginalis lysates also activated HIV expression in certain T cell lines. G. vaginalis lysates activated HIV long-terminal repeat transcription in HIV-infected cells and increased NF-kappaB binding activity, indicating an effect by G. vaginalis on HIV transcription. The activation of HIV production by G. vaginalis suggests that genital tract infection with G. vaginalis increases the risk of HIV transmission by increasing HIV expression in the genital tract. This may explain, at least in part, the increased rate of HIV transmission in women with BV. " ], "offsets": [ [ 0, 1107 ] ] } ]

[]

[]

[]

[]

[ { "id": "PMID-10068671__text", "type": "abstract", "text": [ "Interferon-alpha activates multiple STAT proteins and upregulates proliferation-associated IL-2Ralpha, c-myc, and pim-1 genes in human T cells. \nInterferon-alpha (IFN-alpha) is a pleiotropic cytokine that has antiviral, antiproliferative, and immunoregulatory functions. There is increasing evidence that IFN-alpha has an important role in T-cell biology. We have analyzed the expression of IL-2Ralpha, c-myc, and pim-1 genes in anti-CD3-activated human T lymphocytes. The induction of these genes is associated with interleukin-2 (IL-2)-induced T-cell proliferation. Treatment of T lymphocytes with IFN-alpha, IL-2, IL-12, and IL-15 upregulated IL-2Ralpha, c-myc, and pim-1 gene expression. IFN-alpha also sensitized T cells to IL-2-induced proliferation, further suggesting that IFN-alpha may be involved in the regulation of T-cell mitogenesis. When we analyzed the nature of STAT proteins capable of binding to IL-2Ralpha, pim-1, and IRF-1 GAS elements after cytokine stimulation, we observed IFN-alpha-induced binding of STAT1, STAT3, and STAT4, but not STAT5 to all of these elements. Yet, IFN-alpha was able to activate binding of STAT5 to the high-affinity IFP53 GAS site. IFN-alpha enhanced tyrosine phosphorylation of STAT1, STAT3, STAT4, STAT5a, and STAT5b. IL-12 induced STAT4 and IL-2 and IL-15 induced STAT5 binding to the GAS elements. Taken together, our results suggest that IFN-alpha, IL-2, IL-12, and IL-15 have overlapping activities on human T cells. These findings thus emphasize the importance of IFN-alpha as a T-cell regulatory cytokine. " ], "offsets": [ [ 0, 1563 ] ] } ]

[ { "id": "PMID-10068671_T1", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 91, 101 ] ], "normalized": [] }, { "id": "PMID-10068671_T2", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 103, 108 ] ], "normalized": [] }, { "id": "PMID-10068671_T3", "type": "Protein", "text": [ "pim-1" ], "offsets": [ [ 114, 119 ] ], "normalized": [] }, { "id": "PMID-10068671_T4", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 391, 401 ] ], "normalized": [] }, { "id": "PMID-10068671_T5", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 403, 408 ] ], "normalized": [] }, { "id": "PMID-10068671_T6", "type": "Protein", "text": [ "pim-1" ], "offsets": [ [ 414, 419 ] ], "normalized": [] }, { "id": "PMID-10068671_T7", "type": "Protein", "text": [ "interleukin-2" ], "offsets": [ [ 517, 530 ] ], "normalized": [] }, { "id": "PMID-10068671_T8", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 532, 536 ] ], "normalized": [] }, { "id": "PMID-10068671_T9", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 611, 615 ] ], "normalized": [] }, { "id": "PMID-10068671_T10", "type": "Protein", "text": [ "IL-15" ], "offsets": [ [ 628, 633 ] ], "normalized": [] }, { "id": "PMID-10068671_T11", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 646, 656 ] ], "normalized": [] }, { "id": "PMID-10068671_T12", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 658, 663 ] ], "normalized": [] }, { "id": "PMID-10068671_T13", "type": "Protein", "text": [ "pim-1" ], "offsets": [ [ 669, 674 ] ], "normalized": [] }, { "id": "PMID-10068671_T14", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 729, 733 ] ], "normalized": [] }, { "id": "PMID-10068671_T15", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 915, 925 ] ], "normalized": [] }, { "id": "PMID-10068671_T16", "type": "Protein", "text": [ "pim-1" ], "offsets": [ [ 927, 932 ] ], "normalized": [] }, { "id": "PMID-10068671_T17", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 938, 943 ] ], "normalized": [] }, { "id": "PMID-10068671_T18", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 1026, 1031 ] ], "normalized": [] }, { "id": "PMID-10068671_T19", "type": "Protein", "text": [ "STAT3" ], "offsets": [ [ 1033, 1038 ] ], "normalized": [] }, { "id": "PMID-10068671_T20", "type": "Protein", "text": [ "STAT4" ], "offsets": [ [ 1044, 1049 ] ], "normalized": [] }, { "id": "PMID-10068671_T21", "type": "Protein", "text": [ "IFP53" ], "offsets": [ [ 1165, 1170 ] ], "normalized": [] }, { "id": "PMID-10068671_T22", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 1228, 1233 ] ], "normalized": [] }, { "id": "PMID-10068671_T23", "type": "Protein", "text": [ "STAT3" ], "offsets": [ [ 1235, 1240 ] ], "normalized": [] }, { "id": "PMID-10068671_T24", "type": "Protein", "text": [ "STAT4" ], "offsets": [ [ 1242, 1247 ] ], "normalized": [] }, { "id": "PMID-10068671_T25", "type": "Protein", "text": [ "STAT5a" ], "offsets": [ [ 1249, 1255 ] ], "normalized": [] }, { "id": "PMID-10068671_T26", "type": "Protein", "text": [ "STAT5b" ], "offsets": [ [ 1261, 1267 ] ], "normalized": [] }, { "id": "PMID-10068671_T27", "type": "Protein", "text": [ "STAT4" ], "offsets": [ [ 1283, 1288 ] ], "normalized": [] }, { "id": "PMID-10068671_T28", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1293, 1297 ] ], "normalized": [] }, { "id": "PMID-10068671_T29", "type": "Protein", "text": [ "IL-15" ], "offsets": [ [ 1302, 1307 ] ], "normalized": [] }, { "id": "PMID-10068671_T30", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1403, 1407 ] ], "normalized": [] }, { "id": "PMID-10068671_T31", "type": "Protein", "text": [ "IL-15" ], "offsets": [ [ 1420, 1425 ] ], "normalized": [] }, { "id": "PMID-10068671_T38", "type": "Entity", "text": [ "GAS elements" ], "offsets": [ [ 944, 956 ] ], "normalized": [] }, { "id": "PMID-10068671_T42", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 1200, 1208 ] ], "normalized": [] } ]

[ { "id": "PMID-10068671_E1", "type": "Positive_regulation", "trigger": { "text": [ "upregulates" ], "offsets": [ [ 54, 65 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T3" } ] }, { "id": "PMID-10068671_E2", "type": "Positive_regulation", "trigger": { "text": [ "upregulates" ], "offsets": [ [ 54, 65 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T1" } ] }, { "id": "PMID-10068671_E3", "type": "Positive_regulation", "trigger": { "text": [ "upregulates" ], "offsets": [ [ 54, 65 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T2" } ] }, { "id": "PMID-10068671_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 377, 387 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T6" } ] }, { "id": "PMID-10068671_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 377, 387 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T4" } ] }, { "id": "PMID-10068671_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 377, 387 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T5" } ] }, { "id": "PMID-10068671_E7", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 473, 482 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T4" } ] }, { "id": "PMID-10068671_E8", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 473, 482 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T6" } ] }, { "id": "PMID-10068671_E9", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 473, 482 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T5" } ] }, { "id": "PMID-10068671_E10", "type": "Positive_regulation", "trigger": { "text": [ "upregulated" ], "offsets": [ [ 634, 645 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E14" } ] }, { "id": "PMID-10068671_E11", "type": "Positive_regulation", "trigger": { "text": [ "upregulated" ], "offsets": [ [ 634, 645 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E13" } ] }, { "id": "PMID-10068671_E12", "type": "Positive_regulation", "trigger": { "text": [ "upregulated" ], "offsets": [ [ 634, 645 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E15" } ] }, { "id": "PMID-10068671_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 680, 690 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T13" } ] }, { "id": "PMID-10068671_E14", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 680, 690 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T12" } ] }, { "id": "PMID-10068671_E15", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 680, 690 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T11" } ] }, { "id": "PMID-10068671_E16", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 904, 911 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T16" }, { "role": "Site", "ref_id": "PMID-10068671_T38" } ] }, { "id": "PMID-10068671_E17", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 904, 911 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T15" }, { "role": "Site", "ref_id": "PMID-10068671_T38" } ] }, { "id": "PMID-10068671_E18", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 904, 911 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T17" }, { "role": "Site", "ref_id": "PMID-10068671_T38" } ] }, { "id": "PMID-10068671_E19", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1007, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E33" } ] }, { "id": "PMID-10068671_E20", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1007, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E35" } ] }, { "id": "PMID-10068671_E21", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1007, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E34" } ] }, { "id": "PMID-10068671_E22", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1007, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E32" } ] }, { "id": "PMID-10068671_E23", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1007, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E42" } ] }, { "id": "PMID-10068671_E24", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1007, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E38" } ] }, { "id": "PMID-10068671_E25", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1007, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E31" } ] }, { "id": "PMID-10068671_E26", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1007, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E37" } ] }, { "id": "PMID-10068671_E27", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1007, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E39" } ] }, { "id": "PMID-10068671_E28", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1007, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E36" } ] }, { "id": "PMID-10068671_E29", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1007, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E41" } ] }, { "id": "PMID-10068671_E30", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1007, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E40" } ] }, { "id": "PMID-10068671_E31", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1015, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T17" }, { "role": "Theme", "ref_id": "PMID-10068671_T20" }, { "role": "Site", "ref_id": "PMID-10068671_T38" } ] }, { "id": "PMID-10068671_E32", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1015, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T15" }, { "role": "Theme", "ref_id": "PMID-10068671_T19" }, { "role": "Site", "ref_id": "PMID-10068671_T38" } ] }, { "id": "PMID-10068671_E33", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1015, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T17" }, { "role": "Theme", "ref_id": "PMID-10068671_T19" }, { "role": "Site", "ref_id": "PMID-10068671_T38" } ] }, { "id": "PMID-10068671_E34", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1015, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T16" }, { "role": "Theme", "ref_id": "PMID-10068671_T20" }, { "role": "Site", "ref_id": "PMID-10068671_T38" } ] }, { "id": "PMID-10068671_E35", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1015, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T15" }, { "role": "Theme", "ref_id": "PMID-10068671_T18" }, { "role": "Site", "ref_id": "PMID-10068671_T38" } ] }, { "id": "PMID-10068671_E36", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1015, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T15" }, { "role": "Theme", "ref_id": "PMID-10068671_T20" }, { "role": "Site", "ref_id": "PMID-10068671_T38" } ] }, { "id": "PMID-10068671_E37", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1015, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T15" }, { "role": "Site", "ref_id": "PMID-10068671_T38" } ] }, { "id": "PMID-10068671_E38", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1015, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T16" }, { "role": "Site", "ref_id": "PMID-10068671_T38" } ] }, { "id": "PMID-10068671_E39", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1015, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T17" }, { "role": "Theme", "ref_id": "PMID-10068671_T18" }, { "role": "Site", "ref_id": "PMID-10068671_T38" } ] }, { "id": "PMID-10068671_E40", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1015, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T16" }, { "role": "Theme", "ref_id": "PMID-10068671_T19" }, { "role": "Site", "ref_id": "PMID-10068671_T38" } ] }, { "id": "PMID-10068671_E41", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1015, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T17" }, { "role": "Site", "ref_id": "PMID-10068671_T38" } ] }, { "id": "PMID-10068671_E42", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1015, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T16" }, { "role": "Theme", "ref_id": "PMID-10068671_T18" }, { "role": "Site", "ref_id": "PMID-10068671_T38" } ] }, { "id": "PMID-10068671_E43", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1191, 1199 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E49" } ] }, { "id": "PMID-10068671_E44", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1191, 1199 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E50" } ] }, { "id": "PMID-10068671_E45", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1191, 1199 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E51" } ] }, { "id": "PMID-10068671_E46", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1191, 1199 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E48" } ] }, { "id": "PMID-10068671_E47", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1191, 1199 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E52" } ] }, { "id": "PMID-10068671_E48", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1209, 1224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T22" }, { "role": "Site", "ref_id": "PMID-10068671_T42" } ] }, { "id": "PMID-10068671_E49", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1209, 1224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T23" }, { "role": "Site", "ref_id": "PMID-10068671_T42" } ] }, { "id": "PMID-10068671_E50", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1209, 1224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T25" }, { "role": "Site", "ref_id": "PMID-10068671_T42" } ] }, { "id": "PMID-10068671_E51", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1209, 1224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T24" }, { "role": "Site", "ref_id": "PMID-10068671_T42" } ] }, { "id": "PMID-10068671_E52", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1209, 1224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T26" }, { "role": "Site", "ref_id": "PMID-10068671_T42" } ] }, { "id": "PMID-10068671_E53", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1275, 1282 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_E54" } ] }, { "id": "PMID-10068671_E54", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1322, 1329 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10068671_T27" } ] } ]

[ { "id": "PMID-10068671_1", "entity_ids": [ "PMID-10068671_T7", "PMID-10068671_T8" ] } ]

[]

[ { "id": "PMID-10069412__text", "type": "abstract", "text": [ "Anti-rheumatic compound aurothioglucose inhibits tumor necrosis factor-alpha-induced HIV-1 replication in latently infected OM10.1 and Ach2 cells. \nNF-kappaB is a potent cellular activator of HIV-1 gene expression. Down-regulation of NF-kappaB activation is known to inhibit HIV replication from the latently infected cells. Gold compounds have been effectively used for many decades in the treatment of rheumatoid arthritis. We previously reported that gold compounds, especially aurothioglucose (AuTG) containing monovalent gold ion, inhibited the DNA-binding of NF-kappaB in vitro. In this report we have examined the efficacy of the gold compound AuTG as an inhibitor of HIV replication in latently infected OM10.1 and Ach2 cells. Tumor necrosis factor (TNF)-alpha-induced HIV-1 replication in OM10.1 or Ach2 cells was significantly inhibited by non-cytotoxic doses of AuTG (>10 microM in OM10.1 cells and >25 F.M in Ach2 cells), while 25 microM of the counter-anion thioglucose (TG) or gold compound containing divalent gold ion, HAuCl3, had no effect. The effect of AuTG on NF-kappaB-dependent gene expression was confirmed by a transient CAT assay. Specific staining as well as electron microscopic examinations revealed the accumulation of metal gold in the cells, supporting our previous hypothesis that gold ions could block NF-kappaB-DNA binding by a redox mechanism. These observations indicate that the monovalent gold compound AuTG is a potentially useful drug for the treatment of patients infected with HIV. " ], "offsets": [ [ 0, 1524 ] ] } ]

[ { "id": "PMID-10069412_T1", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 49, 76 ] ], "normalized": [] }, { "id": "PMID-10069412_T2", "type": "Protein", "text": [ "Tumor necrosis factor (TNF)-alpha" ], "offsets": [ [ 735, 768 ] ], "normalized": [] }, { "id": "PMID-10069412_T3", "type": "Protein", "text": [ "CAT" ], "offsets": [ [ 1145, 1148 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-10069428__text", "type": "abstract", "text": [ "Evidence for suppressed activity of the transcription factor NFAT1 at its proximal binding element P0 in the IL-4 promoter associated with enhanced IL-4 gene transcription in T cells of atopic patients. \nAllergen-specific T cells in atopic patients are polarized IL-4-producing Th2 cells, promoting IgE synthesis by B cells. The molecular basis for increased IL-4 gene expression in atopy is not fully understood. IL-4 gene regulation in general involves the nuclear factor of activated T cells (NFAT) family of transcription factors, of which NFAT1 and NFAT2 are most prominent in peripheral T cells. Recently, a unique inhibitory role of NFAT1 in IL-4 gene control was shown in the mouse. In a series of electrophoretic mobility shift assays with protein extracts of highly polarized Th2 clones from atopics and Th1 clones from controls we compared DNA-binding activities at the two NFAT-binding elements P0 and P1 of the crucial proximal human IL-4 promoter. At the most proximal P0 site, NFAT-containing complexes devoid of NFAT2 were readily inducible in the Th1 clones, but hardly or not in the Th2 clones. In contrast, both in Th1 and Th2 clones NFAT-containing complexes were strongly inducible at the P1 site, consisting of NFAT2 and a P0-compatible NFAT activity, without apparent differences between Th1 and Th2 clones. Like in Th2 clones, suppressed NFAT-P0 complex formation was observed also at the polyclonal level in peripheral blood mononuclear cells (PBMC) of three of five severe atopic dermatitis patients with strongly elevated serum IgE levels, but not in control PBMC. These findings suggest that high-level IL-4 production in atopic Th2 cells is associated with selective reduction of suppressive NFAT1 activity at the IL-4 P0 element and that some patients with this multifactorial disease may have a putative systemic disorder at this level. " ], "offsets": [ [ 0, 1868 ] ] } ]

[ { "id": "PMID-10069428_T1", "type": "Protein", "text": [ "NFAT1" ], "offsets": [ [ 61, 66 ] ], "normalized": [] }, { "id": "PMID-10069428_T2", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 109, 113 ] ], "normalized": [] }, { "id": "PMID-10069428_T3", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 148, 152 ] ], "normalized": [] }, { "id": "PMID-10069428_T4", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 263, 267 ] ], "normalized": [] }, { "id": "PMID-10069428_T5", "type": "Protein", "text": [ "IgE" ], "offsets": [ [ 299, 302 ] ], "normalized": [] }, { "id": "PMID-10069428_T6", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 359, 363 ] ], "normalized": [] }, { "id": "PMID-10069428_T7", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 414, 418 ] ], "normalized": [] }, { "id": "PMID-10069428_T8", "type": "Protein", "text": [ "NFAT1" ], "offsets": [ [ 544, 549 ] ], "normalized": [] }, { "id": "PMID-10069428_T9", "type": "Protein", "text": [ "NFAT2" ], "offsets": [ [ 554, 559 ] ], "normalized": [] }, { "id": "PMID-10069428_T10", "type": "Protein", "text": [ "NFAT1" ], "offsets": [ [ 640, 645 ] ], "normalized": [] }, { "id": "PMID-10069428_T11", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 649, 653 ] ], "normalized": [] }, { "id": "PMID-10069428_T12", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 947, 951 ] ], "normalized": [] }, { "id": "PMID-10069428_T13", "type": "Protein", "text": [ "NFAT2" ], "offsets": [ [ 1028, 1033 ] ], "normalized": [] }, { "id": "PMID-10069428_T14", "type": "Protein", "text": [ "NFAT2" ], "offsets": [ [ 1233, 1238 ] ], "normalized": [] }, { "id": "PMID-10069428_T15", "type": "Protein", "text": [ "IgE" ], "offsets": [ [ 1555, 1558 ] ], "normalized": [] }, { "id": "PMID-10069428_T16", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1631, 1635 ] ], "normalized": [] }, { "id": "PMID-10069428_T17", "type": "Protein", "text": [ "NFAT1" ], "offsets": [ [ 1721, 1726 ] ], "normalized": [] }, { "id": "PMID-10069428_T18", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1743, 1747 ] ], "normalized": [] }, { "id": "PMID-10069428_T20", "type": "Entity", "text": [ "proximal binding element P0" ], "offsets": [ [ 74, 101 ] ], "normalized": [] } ]

[ { "id": "PMID-10069428_E1", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 13, 23 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_T1" }, { "role": "Cause", "ref_id": "PMID-10069428_E2" } ] }, { "id": "PMID-10069428_E2", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 83, 90 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_T1" }, { "role": "Theme", "ref_id": "PMID-10069428_T2" }, { "role": "Site", "ref_id": "PMID-10069428_T20" } ] }, { "id": "PMID-10069428_E3", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 139, 147 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_E4" } ] }, { "id": "PMID-10069428_E4", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 158, 171 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_T3" } ] }, { "id": "PMID-10069428_E5", "type": "Gene_expression", "trigger": { "text": [ "producing" ], "offsets": [ [ 268, 277 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_T4" } ] }, { "id": "PMID-10069428_E6", "type": "Positive_regulation", "trigger": { "text": [ "promoting" ], "offsets": [ [ 289, 298 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_E7" }, { "role": "Cause", "ref_id": "PMID-10069428_E5" } ] }, { "id": "PMID-10069428_E7", "type": "Gene_expression", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 303, 312 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_T5" } ] }, { "id": "PMID-10069428_E8", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 349, 358 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_E9" } ] }, { "id": "PMID-10069428_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 369, 379 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_T6" } ] }, { "id": "PMID-10069428_E10", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 424, 434 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_T7" } ] }, { "id": "PMID-10069428_E11", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 446, 454 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_E10" }, { "role": "Cause", "ref_id": "PMID-10069428_T9" } ] }, { "id": "PMID-10069428_E12", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 446, 454 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_E10" }, { "role": "Cause", "ref_id": "PMID-10069428_T8" } ] }, { "id": "PMID-10069428_E13", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory role" ], "offsets": [ [ 621, 636 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_E14" }, { "role": "Cause", "ref_id": "PMID-10069428_T10" } ] }, { "id": "PMID-10069428_E14", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 659, 666 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_T11" } ] }, { "id": "PMID-10069428_E15", "type": "Binding", "trigger": { "text": [ "complexes" ], "offsets": [ [ 1008, 1017 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_T13" } ] }, { "id": "PMID-10069428_E16", "type": "Binding", "trigger": { "text": [ "complexes" ], "offsets": [ [ 1169, 1178 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_T14" } ] }, { "id": "PMID-10069428_E17", "type": "Positive_regulation", "trigger": { "text": [ "inducible" ], "offsets": [ [ 1193, 1202 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_E16" } ] }, { "id": "PMID-10069428_E18", "type": "Positive_regulation", "trigger": { "text": [ "elevated" ], "offsets": [ [ 1540, 1548 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_E19" } ] }, { "id": "PMID-10069428_E19", "type": "Gene_expression", "trigger": { "text": [ "levels" ], "offsets": [ [ 1559, 1565 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_T15" } ] }, { "id": "PMID-10069428_E20", "type": "Positive_regulation", "trigger": { "text": [ "high-level" ], "offsets": [ [ 1620, 1630 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_E21" } ] }, { "id": "PMID-10069428_E21", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 1636, 1646 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10069428_T16" } ] } ]

[]

[]

[ { "id": "PMID-10070274__text", "type": "abstract", "text": [ "Nuclear factor-kappa B activity in T cells from patients with rheumatic diseases: a preliminary report. \nOBJECTIVE: The NF-kappa B/Rel family of transcription factors regulates the expression of many genes involved in the immune or inflammatory response at the transcriptional level. The aim of this study was to determine whether distinctive patterns of NF-kappa B activation are seen in different forms of joint disease. METHODS: The DNA binding activity of these nucleoproteins was examined in purified synovial and peripheral T cells from patients with various chronic rheumatic diseases (12: four with rheumatoid arthritis; five with spondyloarthropathies; and three with osteoarthritis). RESULTS: Electrophoretic mobility shift assays disclosed two specific complexes bound to a NF-kappa B specific 32P-labelled oligonucleotide in nucleoproteins extracted from purified T cells isolated from synovial fluid and peripheral blood of patients with rheumatoid arthritis. The complexes consisted of p50/p50 homodimers and p50/p65 heterodimers. Increased NF-kappa B binding to DNA in synovial T cells was observed relative to peripheral T cells. In non-rheumatoid arthritis, binding of NF-kappa B in synovial T cells was exclusively mediated by p50/p50 homodimers. CONCLUSION: Overall, the results suggest that NF-kappa B may play a central part in the activation of infiltrating T cells in chronic rheumatoid arthritis. The activation of this nuclear factor is qualitatively different in rheumatoid synovial T cells to that in other forms of non-rheumatoid arthritis (for example, osteoarthritis, spondyloarthropathies). " ], "offsets": [ [ 0, 1622 ] ] } ]

[ { "id": "PMID-10070274_T1", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1000, 1003 ] ], "normalized": [] }, { "id": "PMID-10070274_T2", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1004, 1007 ] ], "normalized": [] }, { "id": "PMID-10070274_T3", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1023, 1026 ] ], "normalized": [] }, { "id": "PMID-10070274_T4", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1027, 1030 ] ], "normalized": [] }, { "id": "PMID-10070274_T5", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1245, 1248 ] ], "normalized": [] }, { "id": "PMID-10070274_T6", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1249, 1252 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-10070274_1", "entity_ids": [ "PMID-10070274_T5", "PMID-10070274_T6" ] }, { "id": "PMID-10070274_2", "entity_ids": [ "PMID-10070274_T1", "PMID-10070274_T2" ] } ]

[]

[ { "id": "PMID-10072497__text", "type": "abstract", "text": [ "N-acetyl-L-cysteine inhibits primary human T cell responses at the dendritic cell level: association with NF-kappaB inhibition. \nN-acetyl-L-cysteine (NAC) is an antioxidant molecule endowed with immunomodulatory properties. To investigate the effect of NAC on the induction phase of T cell responses, we analyzed its action on human dendritic cells (DC) derived from adherent PBMC cultured with IL-4 and granulocyte-macrophage CSF. We first found that NAC inhibited the constitutive as well as the LPS-induced activity of the transcription factor NF-kappaB. In parallel, NAC was shown to down-regulate the production of cytokines by DC as well as their surface expression of HLA-DR, CD86 (B7-2), and CD40 molecules both at the basal state and upon LPS activation. NAC also inhibited DC responses induced by CD40 engagement. The inhibitory effects of NAC were not due to nonspecific toxicity as neither the viability of DC nor their mannose receptor-mediated endocytosis were modified by NAC. Finally, we found that the addition of NAC to MLR between naive T cells and allogeneic DC resulted in a profound inhibition of alloreactive responses, which could be attributed to a defect of DC as APC-independent T cell responses were not inhibited by NAC. Altogether, our results suggest that NAC might impair the generation of primary immune responses in humans through its inhibitory action on DC. " ], "offsets": [ [ 0, 1394 ] ] } ]

[ { "id": "PMID-10072497_T1", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 395, 399 ] ], "normalized": [] }, { "id": "PMID-10072497_T2", "type": "Protein", "text": [ "granulocyte-macrophage CSF" ], "offsets": [ [ 404, 430 ] ], "normalized": [] }, { "id": "PMID-10072497_T3", "type": "Protein", "text": [ "CD86" ], "offsets": [ [ 683, 687 ] ], "normalized": [] }, { "id": "PMID-10072497_T4", "type": "Protein", "text": [ "B7-2" ], "offsets": [ [ 689, 693 ] ], "normalized": [] }, { "id": "PMID-10072497_T5", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 700, 704 ] ], "normalized": [] }, { "id": "PMID-10072497_T6", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 807, 811 ] ], "normalized": [] }, { "id": "PMID-10072497_T7", "type": "Protein", "text": [ "mannose receptor" ], "offsets": [ [ 932, 948 ] ], "normalized": [] } ]

[ { "id": "PMID-10072497_E1", "type": "Negative_regulation", "trigger": { "text": [ "down-regulate" ], "offsets": [ [ 588, 601 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10072497_E5" } ] }, { "id": "PMID-10072497_E2", "type": "Negative_regulation", "trigger": { "text": [ "down-regulate" ], "offsets": [ [ 588, 601 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10072497_E6" } ] }, { "id": "PMID-10072497_E3", "type": "Negative_regulation", "trigger": { "text": [ "down-regulate" ], "offsets": [ [ 588, 601 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10072497_E7" } ] }, { "id": "PMID-10072497_E4", "type": "Negative_regulation", "trigger": { "text": [ "down-regulate" ], "offsets": [ [ 588, 601 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10072497_E8" } ] }, { "id": "PMID-10072497_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 661, 671 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10072497_T3" } ] }, { "id": "PMID-10072497_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 661, 671 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10072497_T5" } ] }, { "id": "PMID-10072497_E7", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 752, 762 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10072497_E5" } ] }, { "id": "PMID-10072497_E8", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 752, 762 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10072497_E6" } ] }, { "id": "PMID-10072497_E9", "type": "Binding", "trigger": { "text": [ "engagement" ], "offsets": [ [ 812, 822 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10072497_T6" } ] } ]

[ { "id": "PMID-10072497_1", "entity_ids": [ "PMID-10072497_T3", "PMID-10072497_T4" ] } ]

[]

[ { "id": "PMID-10075645__text", "type": "abstract", "text": [ "Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. \nBacterial lipopolysaccharide (LPS)-mediated immune responses, including activation of monocytes, macrophages, and endothelial cells, play an important role in the pathogenesis of Gram-negative bacteria-induced sepsis syndrome. Activation of NF-kappaB is thought to be required for cytokine release from LPS-responsive cells, a critical step for endotoxic effects. Here we investigated the role and involvement of interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha) signal transducer molecules in LPS signaling in human dermal microvessel endothelial cells (HDMEC) and THP-1 monocytic cells. LPS stimulation of HDMEC and THP-1 cells initiated an IL-1 receptor-like NF-kappaB signaling cascade. In transient cotransfection experiments, dominant negative mutants of the IL-1 signaling pathway, including MyD88, IRAK, IRAK2, and TRAF6 inhibited both IL-1- and LPS-induced NF-kappaB-luciferase activity. LPS-induced NF-kappaB activation was not inhibited by a dominant negative mutant of TRAF2 that is involved in TNF signaling. LPS-induced activation of NF-kappaB-responsive reporter gene was not inhibited by IL-1 receptor antagonist. TLR2 and TLR4 were expressed on the cell surface of HDMEC and THP-1 cells. These findings suggest that a signal transduction molecule in the LPS receptor complex may belong to the IL-1 receptor/toll-like receptor (TLR) super family, and the LPS signaling cascade uses an analogous molecular framework for signaling as IL-1 in mononuclear phagocytes and endothelial cells. " ], "offsets": [ [ 0, 1686 ] ] } ]

[ { "id": "PMID-10075645_T1", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 636, 645 ] ], "normalized": [] }, { "id": "PMID-10075645_T2", "type": "Protein", "text": [ "MyD88" ], "offsets": [ [ 983, 988 ] ], "normalized": [] }, { "id": "PMID-10075645_T3", "type": "Protein", "text": [ "IRAK" ], "offsets": [ [ 990, 994 ] ], "normalized": [] }, { "id": "PMID-10075645_T4", "type": "Protein", "text": [ "IRAK2" ], "offsets": [ [ 996, 1001 ] ], "normalized": [] }, { "id": "PMID-10075645_T5", "type": "Protein", "text": [ "TRAF6" ], "offsets": [ [ 1007, 1012 ] ], "normalized": [] }, { "id": "PMID-10075645_T6", "type": "Protein", "text": [ "TRAF2" ], "offsets": [ [ 1165, 1170 ] ], "normalized": [] }, { "id": "PMID-10075645_T7", "type": "Protein", "text": [ "TLR2" ], "offsets": [ [ 1314, 1318 ] ], "normalized": [] }, { "id": "PMID-10075645_T8", "type": "Protein", "text": [ "TLR4" ], "offsets": [ [ 1323, 1327 ] ], "normalized": [] } ]

[ { "id": "PMID-10075645_E1", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1333, 1342 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10075645_T8" } ] }, { "id": "PMID-10075645_E2", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1333, 1342 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10075645_T7" } ] } ]

[]

[]

[ { "id": "PMID-10079106__text", "type": "abstract", "text": [ "Selective activation and functional significance of p38alpha mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophils. \nActivation of leukocytes by proinflammatory stimuli selectively initiates intracellular signal transduction via sequential phosphorylation of kinases. Lipopolysaccharide (LPS) stimulation of human neutrophils is known to result in activation of p38 mitogen-activated protein kinase (MAPk); however, the upstream activator(s) of p38 MAPk is unknown, and consequences of p38 MAPk activation remain largely undefined. We investigated the MAPk kinase (MKK) that activates p38 MAPk in response to LPS, the p38 MAPk isoforms that are activated as part of this pathway, and the functional responses affected by p38 MAPk activation. Although MKK3, MKK4, and MKK6 all activated p38 MAPk in experimental models, only MKK3 was found to activate recombinant p38 MAPk in LPS-treated neutrophils. Of p38 MAPk isoforms studied, only p38alpha and p38delta were detected in neutrophils. LPS stimulation selectively activated p38alpha. Specific inhibitors of p38alpha MAPk blocked LPS-induced adhesion, nuclear factor-kappa B (NF-kappaB) activation, and synthesis of tumor necrosis factor-alpha (TNF-alpha). Inhibition of p38alpha MAPk resulted in a transient decrease in TNF-alpha mRNA accumulation but persistent loss of TNF-alpha synthesis. These findings support a pathway by which LPS stimulation of neutrophils results in activation of MKK3, which in turn activates p38alpha MAPk, ultimately regulating adhesion, NF-kappaB activation, enhanced gene expression of TNF-alpha, and regulation of TNF-alpha synthesis. " ], "offsets": [ [ 0, 1642 ] ] } ]

[ { "id": "PMID-10079106_T1", "type": "Protein", "text": [ "MKK3" ], "offsets": [ [ 775, 779 ] ], "normalized": [] }, { "id": "PMID-10079106_T2", "type": "Protein", "text": [ "MKK4" ], "offsets": [ [ 781, 785 ] ], "normalized": [] }, { "id": "PMID-10079106_T3", "type": "Protein", "text": [ "MKK6" ], "offsets": [ [ 791, 795 ] ], "normalized": [] }, { "id": "PMID-10079106_T4", "type": "Protein", "text": [ "MKK3" ], "offsets": [ [ 848, 852 ] ], "normalized": [] }, { "id": "PMID-10079106_T5", "type": "Protein", "text": [ "p38alpha" ], "offsets": [ [ 959, 967 ] ], "normalized": [] }, { "id": "PMID-10079106_T6", "type": "Protein", "text": [ "p38delta" ], "offsets": [ [ 972, 980 ] ], "normalized": [] }, { "id": "PMID-10079106_T7", "type": "Protein", "text": [ "p38alpha" ], "offsets": [ [ 1049, 1057 ] ], "normalized": [] }, { "id": "PMID-10079106_T8", "type": "Protein", "text": [ "p38alpha MAPk" ], "offsets": [ [ 1082, 1095 ] ], "normalized": [] }, { "id": "PMID-10079106_T9", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 1190, 1217 ] ], "normalized": [] }, { "id": "PMID-10079106_T10", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1219, 1228 ] ], "normalized": [] }, { "id": "PMID-10079106_T11", "type": "Protein", "text": [ "p38alpha MAPk" ], "offsets": [ [ 1245, 1258 ] ], "normalized": [] }, { "id": "PMID-10079106_T12", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1295, 1304 ] ], "normalized": [] }, { "id": "PMID-10079106_T13", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1346, 1355 ] ], "normalized": [] }, { "id": "PMID-10079106_T14", "type": "Protein", "text": [ "MKK3" ], "offsets": [ [ 1465, 1469 ] ], "normalized": [] }, { "id": "PMID-10079106_T15", "type": "Protein", "text": [ "p38alpha MAPk" ], "offsets": [ [ 1495, 1508 ] ], "normalized": [] }, { "id": "PMID-10079106_T16", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1592, 1601 ] ], "normalized": [] }, { "id": "PMID-10079106_T17", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1621, 1630 ] ], "normalized": [] } ]

[ { "id": "PMID-10079106_E1", "type": "Gene_expression", "trigger": { "text": [ "detected" ], "offsets": [ [ 986, 994 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_T6" } ] }, { "id": "PMID-10079106_E2", "type": "Gene_expression", "trigger": { "text": [ "detected" ], "offsets": [ [ 986, 994 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_T5" } ] }, { "id": "PMID-10079106_E3", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1039, 1048 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_T7" } ] }, { "id": "PMID-10079106_E4", "type": "Negative_regulation", "trigger": { "text": [ "inhibitors" ], "offsets": [ [ 1068, 1078 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_T8" } ] }, { "id": "PMID-10079106_E5", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1096, 1103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_E6" }, { "role": "Cause", "ref_id": "PMID-10079106_E4" } ] }, { "id": "PMID-10079106_E6", "type": "Gene_expression", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 1177, 1186 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_T10" } ] }, { "id": "PMID-10079106_E7", "type": "Negative_regulation", "trigger": { "text": [ "Inhibition" ], "offsets": [ [ 1231, 1241 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_T11" } ] }, { "id": "PMID-10079106_E8", "type": "Negative_regulation", "trigger": { "text": [ "loss" ], "offsets": [ [ 1338, 1342 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_E9" }, { "role": "Cause", "ref_id": "PMID-10079106_E7" } ] }, { "id": "PMID-10079106_E9", "type": "Gene_expression", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 1356, 1365 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_T13" } ] }, { "id": "PMID-10079106_E10", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 1440, 1447 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_E11" } ] }, { "id": "PMID-10079106_E11", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1451, 1461 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_T14" } ] }, { "id": "PMID-10079106_E12", "type": "Positive_regulation", "trigger": { "text": [ "activates" ], "offsets": [ [ 1485, 1494 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_T15" }, { "role": "Cause", "ref_id": "PMID-10079106_E10" } ] }, { "id": "PMID-10079106_E13", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1564, 1572 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_E14" }, { "role": "Cause", "ref_id": "PMID-10079106_E12" } ] }, { "id": "PMID-10079106_E14", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1578, 1588 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_T16" } ] }, { "id": "PMID-10079106_E15", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1607, 1617 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_E16" }, { "role": "Cause", "ref_id": "PMID-10079106_E12" } ] }, { "id": "PMID-10079106_E16", "type": "Gene_expression", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 1631, 1640 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10079106_T17" } ] } ]

[ { "id": "PMID-10079106_1", "entity_ids": [ "PMID-10079106_T10", "PMID-10079106_T9" ] } ]

[]

[ { "id": "PMID-10080532__text", "type": "abstract", "text": [ "Inhibition of IL-4-inducible gene expression in human monocytes by type I and type II interferons. \nThe Th2-type cytokines, interleukin-4 (IL-4) and interleukin-13 (IL-13), induce expression of a distinct subset of genes in human monocytes, including FcepsilonRIIb (CD23), 15-lipoxygenase, IL-1 receptor antagonist (IL-1ra), and type I and type II IL-1 receptors (IL-1R). Type I interferons (IFN-alpha and IFN-beta) and type II interferon (IFN-gamma) inhibit induction of these genes by IL-4 and IL-13. However, the mechanism by which IFNs mediate this inhibition has not been defined. In this overview, we discuss the role of the transcription factor, STAT6 (signal transducer and activator of transcription-6) in mediating IL-4- and IL-13-induced gene expression in monocytes. We also discuss our recent findings that type I and type II IFNs suppress IL-4/IL-13-inducible gene expression by inhibiting tyrosine phosphorylation and nuclear translocation of STAT6. The ability of type I and type II IFNs to inhibit IL-4/IL-13-induced STAT6 activity is dose- and time-dependent, and is not unique to monocytes because IFNs induce the same effects in fibroblasts. Inhibition of STAT6 activity is not evident unless cells are preincubated with IFN for at least 1 h before IL-4 stimulation. Furthermore, inhibition can be blocked by actinomycin D, indicating a requirement for de novo transcription. We propose a model in which stimulation of monocytes by IFN activates de novo synthesis of an inhibitory factor, possibly one or more members of the SOCS/ SSI/CIS gene family, capable of suppressing activation of STAT6 by IL-4 and IL-13. Because STAT6 activation plays an essential role in IL-4/IL-13-induced gene expression, the ability of IFN-beta and IFN-gamma to inhibit STAT6 activity provides an explanation for how IFNs can suppress IL-4/IL-13-inducible gene expression. " ], "offsets": [ [ 0, 1874 ] ] } ]

[ { "id": "PMID-10080532_T1", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 14, 18 ] ], "normalized": [] }, { "id": "PMID-10080532_T2", "type": "Protein", "text": [ "interleukin-4" ], "offsets": [ [ 124, 137 ] ], "normalized": [] }, { "id": "PMID-10080532_T3", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 139, 143 ] ], "normalized": [] }, { "id": "PMID-10080532_T4", "type": "Protein", "text": [ "interleukin-13" ], "offsets": [ [ 149, 163 ] ], "normalized": [] }, { "id": "PMID-10080532_T5", "type": "Protein", "text": [ "IL-13" ], "offsets": [ [ 165, 170 ] ], "normalized": [] }, { "id": "PMID-10080532_T6", "type": "Protein", "text": [ "FcepsilonRIIb" ], "offsets": [ [ 251, 264 ] ], "normalized": [] }, { "id": "PMID-10080532_T7", "type": "Protein", "text": [ "CD23" ], "offsets": [ [ 266, 270 ] ], "normalized": [] }, { "id": "PMID-10080532_T8", "type": "Protein", "text": [ "15-lipoxygenase" ], "offsets": [ [ 273, 288 ] ], "normalized": [] }, { "id": "PMID-10080532_T9", "type": "Protein", "text": [ "IL-1 receptor antagonist" ], "offsets": [ [ 290, 314 ] ], "normalized": [] }, { "id": "PMID-10080532_T10", "type": "Protein", "text": [ "IL-1ra" ], "offsets": [ [ 316, 322 ] ], "normalized": [] }, { "id": "PMID-10080532_T11", "type": "Protein", "text": [ "IFN-beta" ], "offsets": [ [ 406, 414 ] ], "normalized": [] }, { "id": "PMID-10080532_T12", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 440, 449 ] ], "normalized": [] }, { "id": "PMID-10080532_T13", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 487, 491 ] ], "normalized": [] }, { "id": "PMID-10080532_T14", "type": "Protein", "text": [ "IL-13" ], "offsets": [ [ 496, 501 ] ], "normalized": [] }, { "id": "PMID-10080532_T15", "type": "Protein", "text": [ "STAT6" ], "offsets": [ [ 653, 658 ] ], "normalized": [] }, { "id": "PMID-10080532_T16", "type": "Protein", "text": [ "signal transducer and activator of transcription-6" ], "offsets": [ [ 660, 710 ] ], "normalized": [] }, { "id": "PMID-10080532_T17", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 725, 729 ] ], "normalized": [] }, { "id": "PMID-10080532_T18", "type": "Protein", "text": [ "IL-13" ], "offsets": [ [ 735, 740 ] ], "normalized": [] }, { "id": "PMID-10080532_T19", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 853, 857 ] ], "normalized": [] }, { "id": "PMID-10080532_T20", "type": "Protein", "text": [ "IL-13" ], "offsets": [ [ 858, 863 ] ], "normalized": [] }, { "id": "PMID-10080532_T21", "type": "Protein", "text": [ "STAT6" ], "offsets": [ [ 958, 963 ] ], "normalized": [] }, { "id": "PMID-10080532_T22", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1015, 1019 ] ], "normalized": [] }, { "id": "PMID-10080532_T23", "type": "Protein", "text": [ "IL-13" ], "offsets": [ [ 1020, 1025 ] ], "normalized": [] }, { "id": "PMID-10080532_T24", "type": "Protein", "text": [ "STAT6" ], "offsets": [ [ 1034, 1039 ] ], "normalized": [] }, { "id": "PMID-10080532_T25", "type": "Protein", "text": [ "STAT6" ], "offsets": [ [ 1176, 1181 ] ], "normalized": [] }, { "id": "PMID-10080532_T26", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1269, 1273 ] ], "normalized": [] }, { "id": "PMID-10080532_T27", "type": "Protein", "text": [ "STAT6" ], "offsets": [ [ 1609, 1614 ] ], "normalized": [] }, { "id": "PMID-10080532_T28", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1618, 1622 ] ], "normalized": [] }, { "id": "PMID-10080532_T29", "type": "Protein", "text": [ "IL-13" ], "offsets": [ [ 1627, 1632 ] ], "normalized": [] }, { "id": "PMID-10080532_T30", "type": "Protein", "text": [ "STAT6" ], "offsets": [ [ 1642, 1647 ] ], "normalized": [] }, { "id": "PMID-10080532_T31", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1686, 1690 ] ], "normalized": [] }, { "id": "PMID-10080532_T32", "type": "Protein", "text": [ "IL-13" ], "offsets": [ [ 1691, 1696 ] ], "normalized": [] }, { "id": "PMID-10080532_T33", "type": "Protein", "text": [ "IFN-beta" ], "offsets": [ [ 1737, 1745 ] ], "normalized": [] }, { "id": "PMID-10080532_T34", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1750, 1759 ] ], "normalized": [] }, { "id": "PMID-10080532_T35", "type": "Protein", "text": [ "STAT6" ], "offsets": [ [ 1771, 1776 ] ], "normalized": [] }, { "id": "PMID-10080532_T36", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1836, 1840 ] ], "normalized": [] }, { "id": "PMID-10080532_T37", "type": "Protein", "text": [ "IL-13" ], "offsets": [ [ 1841, 1846 ] ], "normalized": [] }, { "id": "PMID-10080532_T44", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 904, 912 ] ], "normalized": [] }, { "id": "PMID-10080532_T46", "type": "Entity", "text": [ "nuclear" ], "offsets": [ [ 933, 940 ] ], "normalized": [] } ]

[ { "id": "PMID-10080532_E1", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 173, 179 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E9" }, { "role": "Cause", "ref_id": "PMID-10080532_T4" } ] }, { "id": "PMID-10080532_E2", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 173, 179 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E8" }, { "role": "Cause", "ref_id": "PMID-10080532_T2" } ] }, { "id": "PMID-10080532_E3", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 173, 179 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E8" }, { "role": "Cause", "ref_id": "PMID-10080532_T4" } ] }, { "id": "PMID-10080532_E4", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 173, 179 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E7" }, { "role": "Cause", "ref_id": "PMID-10080532_T2" } ] }, { "id": "PMID-10080532_E5", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 173, 179 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E9" }, { "role": "Cause", "ref_id": "PMID-10080532_T2" } ] }, { "id": "PMID-10080532_E6", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 173, 179 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E7" }, { "role": "Cause", "ref_id": "PMID-10080532_T4" } ] }, { "id": "PMID-10080532_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 180, 190 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T10" } ] }, { "id": "PMID-10080532_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 180, 190 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T7" } ] }, { "id": "PMID-10080532_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 180, 190 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T8" } ] }, { "id": "PMID-10080532_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E31" } ] }, { "id": "PMID-10080532_E11", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E30" }, { "role": "Cause", "ref_id": "PMID-10080532_T12" } ] }, { "id": "PMID-10080532_E12", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E28" }, { "role": "Cause", "ref_id": "PMID-10080532_T12" } ] }, { "id": "PMID-10080532_E13", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E32" }, { "role": "Cause", "ref_id": "PMID-10080532_T11" } ] }, { "id": "PMID-10080532_E14", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E33" }, { "role": "Cause", "ref_id": "PMID-10080532_T11" } ] }, { "id": "PMID-10080532_E15", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E31" }, { "role": "Cause", "ref_id": "PMID-10080532_T11" } ] }, { "id": "PMID-10080532_E16", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E32" }, { "role": "Cause", "ref_id": "PMID-10080532_T12" } ] }, { "id": "PMID-10080532_E17", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E30" } ] }, { "id": "PMID-10080532_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E29" }, { "role": "Cause", "ref_id": "PMID-10080532_T11" } ] }, { "id": "PMID-10080532_E19", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E29" } ] }, { "id": "PMID-10080532_E20", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E32" } ] }, { "id": "PMID-10080532_E21", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E28" } ] }, { "id": "PMID-10080532_E22", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E28" }, { "role": "Cause", "ref_id": "PMID-10080532_T11" } ] }, { "id": "PMID-10080532_E23", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E33" }, { "role": "Cause", "ref_id": "PMID-10080532_T12" } ] }, { "id": "PMID-10080532_E24", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E33" } ] }, { "id": "PMID-10080532_E25", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E31" }, { "role": "Cause", "ref_id": "PMID-10080532_T12" } ] }, { "id": "PMID-10080532_E26", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E30" }, { "role": "Cause", "ref_id": "PMID-10080532_T11" } ] }, { "id": "PMID-10080532_E27", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E29" }, { "role": "Cause", "ref_id": "PMID-10080532_T12" } ] }, { "id": "PMID-10080532_E28", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 459, 468 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T7" }, { "role": "Cause", "ref_id": "PMID-10080532_T13" } ] }, { "id": "PMID-10080532_E29", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 459, 468 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T8" }, { "role": "Cause", "ref_id": "PMID-10080532_T14" } ] }, { "id": "PMID-10080532_E30", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 459, 468 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T10" }, { "role": "Cause", "ref_id": "PMID-10080532_T14" } ] }, { "id": "PMID-10080532_E31", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 459, 468 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T7" }, { "role": "Cause", "ref_id": "PMID-10080532_T14" } ] }, { "id": "PMID-10080532_E32", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 459, 468 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T8" }, { "role": "Cause", "ref_id": "PMID-10080532_T13" } ] }, { "id": "PMID-10080532_E33", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 459, 468 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T10" }, { "role": "Cause", "ref_id": "PMID-10080532_T13" } ] }, { "id": "PMID-10080532_E34", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E14" } ] }, { "id": "PMID-10080532_E35", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E10" } ] }, { "id": "PMID-10080532_E36", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E15" } ] }, { "id": "PMID-10080532_E37", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E12" } ] }, { "id": "PMID-10080532_E38", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E16" } ] }, { "id": "PMID-10080532_E39", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E11" } ] }, { "id": "PMID-10080532_E40", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E13" } ] }, { "id": "PMID-10080532_E41", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E17" } ] }, { "id": "PMID-10080532_E42", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E20" } ] }, { "id": "PMID-10080532_E43", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E21" } ] }, { "id": "PMID-10080532_E44", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E27" } ] }, { "id": "PMID-10080532_E45", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E24" } ] }, { "id": "PMID-10080532_E46", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E26" } ] }, { "id": "PMID-10080532_E47", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E25" } ] }, { "id": "PMID-10080532_E48", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E22" } ] }, { "id": "PMID-10080532_E49", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E23" } ] }, { "id": "PMID-10080532_E50", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E19" } ] }, { "id": "PMID-10080532_E51", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 540, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E18" } ] }, { "id": "PMID-10080532_E52", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 893, 903 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E53" } ] }, { "id": "PMID-10080532_E53", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 913, 928 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T21" }, { "role": "Site", "ref_id": "PMID-10080532_T44" } ] }, { "id": "PMID-10080532_E54", "type": "Localization", "trigger": { "text": [ "translocation" ], "offsets": [ [ 941, 954 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T21" }, { "role": "ToLoc", "ref_id": "PMID-10080532_T46" } ] }, { "id": "PMID-10080532_E55", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1007, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E57" } ] }, { "id": "PMID-10080532_E56", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1007, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E58" } ] }, { "id": "PMID-10080532_E57", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1026, 1033 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T24" }, { "role": "Cause", "ref_id": "PMID-10080532_T22" } ] }, { "id": "PMID-10080532_E58", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1026, 1033 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T24" }, { "role": "Cause", "ref_id": "PMID-10080532_T23" } ] }, { "id": "PMID-10080532_E59", "type": "Negative_regulation", "trigger": { "text": [ "Inhibition" ], "offsets": [ [ 1162, 1172 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T25" } ] }, { "id": "PMID-10080532_E60", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1318, 1325 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E59" } ] }, { "id": "PMID-10080532_E61", "type": "Positive_regulation", "trigger": { "text": [ "requirement" ], "offsets": [ [ 1357, 1368 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E59" } ] }, { "id": "PMID-10080532_E62", "type": "Negative_regulation", "trigger": { "text": [ "suppressing" ], "offsets": [ [ 1583, 1594 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E65" } ] }, { "id": "PMID-10080532_E63", "type": "Negative_regulation", "trigger": { "text": [ "suppressing" ], "offsets": [ [ 1583, 1594 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_E64" } ] }, { "id": "PMID-10080532_E64", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1595, 1605 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T27" }, { "role": "Cause", "ref_id": "PMID-10080532_T28" } ] }, { "id": "PMID-10080532_E65", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1595, 1605 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T27" }, { "role": "Cause", "ref_id": "PMID-10080532_T29" } ] }, { "id": "PMID-10080532_E66", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1648, 1658 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T30" } ] }, { "id": "PMID-10080532_E67", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1763, 1770 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T35" }, { "role": "Cause", "ref_id": "PMID-10080532_T33" } ] }, { "id": "PMID-10080532_E68", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1763, 1770 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080532_T35" }, { "role": "Cause", "ref_id": "PMID-10080532_T34" } ] } ]

[ { "id": "PMID-10080532_1", "entity_ids": [ "PMID-10080532_T15", "PMID-10080532_T16" ] }, { "id": "PMID-10080532_2", "entity_ids": [ "PMID-10080532_T2", "PMID-10080532_T3" ] }, { "id": "PMID-10080532_3", "entity_ids": [ "PMID-10080532_T7", "PMID-10080532_T6" ] }, { "id": "PMID-10080532_4", "entity_ids": [ "PMID-10080532_T10", "PMID-10080532_T9" ] }, { "id": "PMID-10080532_5", "entity_ids": [ "PMID-10080532_T4", "PMID-10080532_T5" ] } ]

[]

[ { "id": "PMID-10080875__text", "type": "abstract", "text": [ "Involvement of NF-kappaB p50/p65 heterodimer in activation of the human pro-interleukin-1beta gene at two subregions of the upstream enhancer element. \nA region between-3134 and -2729 bp upstream from the transcription site of the human pro-interleukin 1beta (proIL-1beta) gene was identified as an LPS-responsive enhancer element. In this study, the influence of the sequences located between -3134 and -2987 on the transcriptional activity of the proIL-1beta gene in LPS-stimulated Raw 264.7 cells was examined in detail. The results obtained by transient transfection of fos -CAT constructs that contained serial 5'-deletion mutations showed that the region between -3134 and -3059 appears to be required for the induction of transcription by LPS. Gel shift assay studies with synthetic oligonucleotides corresponding to partial sequences of the latter region and nuclear extracts from stimulated cells revealed specific protein binding sites between -3110 and -3090 and between -3079 and -3059. These specific bindings were time and LPS dose dependent. The results of supershift analysis using specific antibodies against transcription factors suggested that both binding complexes contained the NF-kappaB components p50 and p65, and did not contain other NF-kappaB proteins (p52, c-Rel, Rel B), AP-1 proteins (c-Fos, C-Jun), CREB or C/EBPbeta (NF-IL6). Mutation of either of the putative NF-kappaB-binding sites in the enhancer element decreased the LPS-stimulated transcriptional activity. These data indicated that two NF-kappaB-binding sites, which are located between -3134 and -3059, are critical for the activation of proIL-1beta gene transcription. Copyright 1999 Academic Press. " ], "offsets": [ [ 0, 1692 ] ] } ]

[ { "id": "PMID-10080875_T1", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 25, 28 ] ], "normalized": [] }, { "id": "PMID-10080875_T2", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 29, 32 ] ], "normalized": [] }, { "id": "PMID-10080875_T3", "type": "Protein", "text": [ "pro-interleukin-1beta" ], "offsets": [ [ 72, 93 ] ], "normalized": [] }, { "id": "PMID-10080875_T4", "type": "Protein", "text": [ "pro-interleukin 1beta" ], "offsets": [ [ 237, 258 ] ], "normalized": [] }, { "id": "PMID-10080875_T5", "type": "Protein", "text": [ "proIL-1beta" ], "offsets": [ [ 260, 271 ] ], "normalized": [] }, { "id": "PMID-10080875_T6", "type": "Protein", "text": [ "proIL-1beta" ], "offsets": [ [ 449, 460 ] ], "normalized": [] }, { "id": "PMID-10080875_T7", "type": "Protein", "text": [ "fos" ], "offsets": [ [ 574, 577 ] ], "normalized": [] }, { "id": "PMID-10080875_T8", "type": "Protein", "text": [ "CAT" ], "offsets": [ [ 579, 582 ] ], "normalized": [] }, { "id": "PMID-10080875_T9", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1221, 1224 ] ], "normalized": [] }, { "id": "PMID-10080875_T10", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1229, 1232 ] ], "normalized": [] }, { "id": "PMID-10080875_T11", "type": "Protein", "text": [ "p52" ], "offsets": [ [ 1280, 1283 ] ], "normalized": [] }, { "id": "PMID-10080875_T12", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 1285, 1290 ] ], "normalized": [] }, { "id": "PMID-10080875_T13", "type": "Protein", "text": [ "Rel B" ], "offsets": [ [ 1292, 1297 ] ], "normalized": [] }, { "id": "PMID-10080875_T14", "type": "Protein", "text": [ "c-Fos" ], "offsets": [ [ 1315, 1320 ] ], "normalized": [] }, { "id": "PMID-10080875_T15", "type": "Protein", "text": [ "C-Jun" ], "offsets": [ [ 1322, 1327 ] ], "normalized": [] }, { "id": "PMID-10080875_T16", "type": "Protein", "text": [ "C/EBPbeta" ], "offsets": [ [ 1338, 1347 ] ], "normalized": [] }, { "id": "PMID-10080875_T17", "type": "Protein", "text": [ "NF-IL6" ], "offsets": [ [ 1349, 1355 ] ], "normalized": [] }, { "id": "PMID-10080875_T18", "type": "Protein", "text": [ "proIL-1beta" ], "offsets": [ [ 1629, 1640 ] ], "normalized": [] } ]

[ { "id": "PMID-10080875_E1", "type": "Positive_regulation", "trigger": { "text": [ "Involvement" ], "offsets": [ [ 0, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080875_E3" }, { "role": "Cause", "ref_id": "PMID-10080875_T2" } ] }, { "id": "PMID-10080875_E2", "type": "Positive_regulation", "trigger": { "text": [ "Involvement" ], "offsets": [ [ 0, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080875_E3" }, { "role": "Cause", "ref_id": "PMID-10080875_T1" } ] }, { "id": "PMID-10080875_E3", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 48, 58 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080875_T3" } ] }, { "id": "PMID-10080875_E4", "type": "Regulation", "trigger": { "text": [ "influence" ], "offsets": [ [ 351, 360 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080875_E5" } ] }, { "id": "PMID-10080875_E5", "type": "Transcription", "trigger": { "text": [ "transcriptional activity" ], "offsets": [ [ 417, 441 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080875_T6" } ] }, { "id": "PMID-10080875_E6", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 716, 725 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080875_E5" } ] }, { "id": "PMID-10080875_E7", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 1441, 1450 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080875_E8" } ] }, { "id": "PMID-10080875_E8", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 1459, 1469 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080875_E5" } ] }, { "id": "PMID-10080875_E9", "type": "Positive_regulation", "trigger": { "text": [ "critical" ], "offsets": [ [ 1598, 1606 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080875_E10" } ] }, { "id": "PMID-10080875_E10", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1615, 1625 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080875_E11" } ] }, { "id": "PMID-10080875_E11", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1646, 1659 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080875_T18" } ] } ]

[ { "id": "PMID-10080875_1", "entity_ids": [ "PMID-10080875_T16", "PMID-10080875_T17" ] }, { "id": "PMID-10080875_2", "entity_ids": [ "PMID-10080875_T4", "PMID-10080875_T5" ] } ]

[]

[ { "id": "PMID-10080948__text", "type": "abstract", "text": [ "Phosphorylation of TRAF2 inhibits binding to the CD40 cytoplasmic domain. \nTRAF2 is a signal transducing adaptor molecule which binds to the CD40 cytoplasmic domain. We have found that it is phosphorylated, predominantly on serine residues, when transiently overexpressed in 293 cells. The phosphorylation appears to be related to the signaling events that are activated by TRAF2 under these circumstances, since two nonfunctional mutants were found to be phosphorylated significantly less than the wild-type protein. Furthermore, the phosphorylation status of TRAF2 had significant effects on the ability of the protein to bind to CD40, as evidenced by our observations that the CD40 cytoplasmic domain interacted preferentially with underphosphorylated TRAF2 and that phosphatase treatment significantly enhanced the binding of TRAF2 to CD40. We conclude from these studies that the phosphorylation of TRAF2 is likely to play an important role in regulating signaling by virtue of its ability to influence the CD40-TRAF2 interaction. Copyright 1999 Academic Press. " ], "offsets": [ [ 0, 1067 ] ] } ]

[ { "id": "PMID-10080948_T1", "type": "Protein", "text": [ "TRAF2" ], "offsets": [ [ 19, 24 ] ], "normalized": [] }, { "id": "PMID-10080948_T2", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 49, 53 ] ], "normalized": [] }, { "id": "PMID-10080948_T3", "type": "Protein", "text": [ "TRAF2" ], "offsets": [ [ 75, 80 ] ], "normalized": [] }, { "id": "PMID-10080948_T4", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 141, 145 ] ], "normalized": [] }, { "id": "PMID-10080948_T5", "type": "Protein", "text": [ "TRAF2" ], "offsets": [ [ 374, 379 ] ], "normalized": [] }, { "id": "PMID-10080948_T6", "type": "Protein", "text": [ "TRAF2" ], "offsets": [ [ 561, 566 ] ], "normalized": [] }, { "id": "PMID-10080948_T7", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 632, 636 ] ], "normalized": [] }, { "id": "PMID-10080948_T8", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 680, 684 ] ], "normalized": [] }, { "id": "PMID-10080948_T9", "type": "Protein", "text": [ "TRAF2" ], "offsets": [ [ 755, 760 ] ], "normalized": [] }, { "id": "PMID-10080948_T10", "type": "Protein", "text": [ "TRAF2" ], "offsets": [ [ 830, 835 ] ], "normalized": [] }, { "id": "PMID-10080948_T11", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 839, 843 ] ], "normalized": [] }, { "id": "PMID-10080948_T12", "type": "Protein", "text": [ "TRAF2" ], "offsets": [ [ 904, 909 ] ], "normalized": [] }, { "id": "PMID-10080948_T13", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 1012, 1016 ] ], "normalized": [] }, { "id": "PMID-10080948_T14", "type": "Protein", "text": [ "TRAF2" ], "offsets": [ [ 1017, 1022 ] ], "normalized": [] }, { "id": "PMID-10080948_T18", "type": "Entity", "text": [ "cytoplasmic domain" ], "offsets": [ [ 54, 72 ] ], "normalized": [] }, { "id": "PMID-10080948_T20", "type": "Entity", "text": [ "cytoplasmic domain" ], "offsets": [ [ 146, 164 ] ], "normalized": [] }, { "id": "PMID-10080948_T22", "type": "Entity", "text": [ "serine residues" ], "offsets": [ [ 224, 239 ] ], "normalized": [] }, { "id": "PMID-10080948_T29", "type": "Entity", "text": [ "cytoplasmic domain" ], "offsets": [ [ 685, 703 ] ], "normalized": [] } ]

[ { "id": "PMID-10080948_E1", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 0, 15 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_T1" } ] }, { "id": "PMID-10080948_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 25, 33 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_E3" }, { "role": "Cause", "ref_id": "PMID-10080948_E1" } ] }, { "id": "PMID-10080948_E3", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 34, 41 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_T1" }, { "role": "Theme", "ref_id": "PMID-10080948_T2" }, { "role": "Site", "ref_id": "PMID-10080948_T18" } ] }, { "id": "PMID-10080948_E4", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 128, 133 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_T3" }, { "role": "Theme", "ref_id": "PMID-10080948_T4" }, { "role": "Site", "ref_id": "PMID-10080948_T20" } ] }, { "id": "PMID-10080948_E5", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 191, 205 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_T3" }, { "role": "Site", "ref_id": "PMID-10080948_T22" } ] }, { "id": "PMID-10080948_E6", "type": "Positive_regulation", "trigger": { "text": [ "when" ], "offsets": [ [ 241, 245 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_E5" }, { "role": "Cause", "ref_id": "PMID-10080948_E7" } ] }, { "id": "PMID-10080948_E7", "type": "Positive_regulation", "trigger": { "text": [ "overexpressed" ], "offsets": [ [ 258, 271 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_E8" } ] }, { "id": "PMID-10080948_E8", "type": "Gene_expression", "trigger": { "text": [ "overexpressed" ], "offsets": [ [ 258, 271 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_T3" } ] }, { "id": "PMID-10080948_E9", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 535, 550 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_T6" } ] }, { "id": "PMID-10080948_E10", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 583, 590 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_E11" }, { "role": "Cause", "ref_id": "PMID-10080948_E9" } ] }, { "id": "PMID-10080948_E11", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 624, 628 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_T6" }, { "role": "Theme", "ref_id": "PMID-10080948_T7" } ] }, { "id": "PMID-10080948_E12", "type": "Binding", "trigger": { "text": [ "interacted" ], "offsets": [ [ 704, 714 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_T8" }, { "role": "Theme", "ref_id": "PMID-10080948_T9" }, { "role": "Site", "ref_id": "PMID-10080948_T29" } ] }, { "id": "PMID-10080948_E13", "type": "Phosphorylation", "trigger": { "text": [ "underphosphorylated" ], "offsets": [ [ 735, 754 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_T9" } ] }, { "id": "PMID-10080948_E14", "type": "Negative_regulation", "trigger": { "text": [ "underphosphorylated" ], "offsets": [ [ 735, 754 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_E13" } ] }, { "id": "PMID-10080948_E15", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 806, 814 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_E16" } ] }, { "id": "PMID-10080948_E16", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 819, 826 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_T10" }, { "role": "Theme", "ref_id": "PMID-10080948_T11" } ] }, { "id": "PMID-10080948_E17", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 885, 900 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_T12" } ] }, { "id": "PMID-10080948_E18", "type": "Regulation", "trigger": { "text": [ "influence" ], "offsets": [ [ 998, 1007 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_E19" }, { "role": "Cause", "ref_id": "PMID-10080948_E17" } ] }, { "id": "PMID-10080948_E19", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1023, 1034 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10080948_T13" }, { "role": "Theme", "ref_id": "PMID-10080948_T14" } ] } ]

[]

[]

[ { "id": "PMID-10082134__text", "type": "abstract", "text": [ "Cobalt chloride-induced signaling in endothelium leading to the augmented adherence of sickle red blood cells and transendothelial migration of monocyte-like HL-60 cells is blocked by PAF-receptor antagonist. \nIn response to hypoxia, sickle red blood cells (SS RBC) and leukocytes exhibit increased adherence to the vascular endothelium, while diapedesis of leukocytes through the blood vessel increases. However, the cellular signaling pathway(s) caused by hypoxia is poorly understood. We utilized CoCl2 as a mimetic molecule for hypoxia to study cellular signaling pathways. We found that in human umbilical vein endothelial cells (HUVEC), CoCl2 at 2 mM concentration induced the surface expression of a subset of CAMs (VCAM-1) and activation of transcription factor NF-kappaB in the nuclear extracts of HUVEC. Furthermore, CoCl2 also caused time-dependent tyrosine phosphorylation of mitogen-activated protein (MAP) kinase isoform ERK2 without significantly affecting ERK1, indicating ERK2 is the preferred substrate for upstream kinase of the MAPK pathway. Inhibitors of MAP kinase (PD98059) or platelet-activating factor (PAF)- receptor antagonist (CV3988) inhibited the CoCl2-induced NF-kappaB activation and VCAM-1 expression. Augmented expression of VCAM-1 led to increased SS RBC adhesion, inhibitable by a VCAM-1 antibody. Additionally, CoCl2 caused a two- to threefold increase in the rate of transendothelial migration of monocyte-like HL-60 cells and a twentyfold increase in phosphorylation of platelet endothelial cell adhesion molecules (PECAM-1). The transendothelial migration of monocytes was inhibited by an antibody to PECAM-1. Both phosphorylation of PECAM-1 and transendothelial migration of monocytes in response to CoCl2 were inhibited by protein kinase inhibitor (GF109203X) and augmented by protein phosphatase inhibitor (Calyculin A). Our data suggests that CoCl2-induced cellular signals directing increased expression of VCAM-1 in HUVEC involve downstream activation of MAP kinase and NF-kappaB, while the phosphorylation of PECAM-1 occurs as a result of activation of PKC. We conclude that PAF-receptor antagonist inhibits the CoCl2- or hypoxia-induced increase in the adhesion of SS RBC, PECAM-1 phosphorylation, and the concomitant transendothelial migration of monocytes. " ], "offsets": [ [ 0, 2307 ] ] } ]

[ { "id": "PMID-10082134_T1", "type": "Protein", "text": [ "PAF-receptor" ], "offsets": [ [ 184, 196 ] ], "normalized": [] }, { "id": "PMID-10082134_T2", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 723, 729 ] ], "normalized": [] }, { "id": "PMID-10082134_T3", "type": "Protein", "text": [ "ERK2" ], "offsets": [ [ 935, 939 ] ], "normalized": [] }, { "id": "PMID-10082134_T4", "type": "Protein", "text": [ "ERK1" ], "offsets": [ [ 972, 976 ] ], "normalized": [] }, { "id": "PMID-10082134_T5", "type": "Protein", "text": [ "ERK2" ], "offsets": [ [ 989, 993 ] ], "normalized": [] }, { "id": "PMID-10082134_T6", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1216, 1222 ] ], "normalized": [] }, { "id": "PMID-10082134_T7", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1259, 1265 ] ], "normalized": [] }, { "id": "PMID-10082134_T8", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1317, 1323 ] ], "normalized": [] }, { "id": "PMID-10082134_T9", "type": "Protein", "text": [ "PECAM-1" ], "offsets": [ [ 1555, 1562 ] ], "normalized": [] }, { "id": "PMID-10082134_T10", "type": "Protein", "text": [ "PECAM-1" ], "offsets": [ [ 1641, 1648 ] ], "normalized": [] }, { "id": "PMID-10082134_T11", "type": "Protein", "text": [ "PECAM-1" ], "offsets": [ [ 1674, 1681 ] ], "normalized": [] }, { "id": "PMID-10082134_T12", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1952, 1958 ] ], "normalized": [] }, { "id": "PMID-10082134_T13", "type": "Protein", "text": [ "PECAM-1" ], "offsets": [ [ 2056, 2063 ] ], "normalized": [] }, { "id": "PMID-10082134_T14", "type": "Protein", "text": [ "PECAM-1" ], "offsets": [ [ 2221, 2228 ] ], "normalized": [] }, { "id": "PMID-10082134_T18", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 860, 868 ] ], "normalized": [] } ]

[ { "id": "PMID-10082134_E1", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 671, 678 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E2" } ] }, { "id": "PMID-10082134_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 691, 701 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_T2" } ] }, { "id": "PMID-10082134_E3", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 838, 844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E4" } ] }, { "id": "PMID-10082134_E4", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 869, 884 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_T3" }, { "role": "Site", "ref_id": "PMID-10082134_T18" } ] }, { "id": "PMID-10082134_E5", "type": "Regulation", "trigger": { "text": [ "affecting" ], "offsets": [ [ 962, 971 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_T4" } ] }, { "id": "PMID-10082134_E6", "type": "Positive_regulation", "trigger": { "text": [ "for" ], "offsets": [ [ 1021, 1024 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E4" } ] }, { "id": "PMID-10082134_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1163, 1172 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E8" } ] }, { "id": "PMID-10082134_E8", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1183, 1190 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E9" } ] }, { "id": "PMID-10082134_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1223, 1233 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_T6" } ] }, { "id": "PMID-10082134_E10", "type": "Positive_regulation", "trigger": { "text": [ "Augmented" ], "offsets": [ [ 1235, 1244 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E11" } ] }, { "id": "PMID-10082134_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1245, 1255 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_T7" } ] }, { "id": "PMID-10082134_E12", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 1354, 1360 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E13" } ] }, { "id": "PMID-10082134_E13", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 1478, 1486 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E14" } ] }, { "id": "PMID-10082134_E14", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1490, 1505 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_T9" } ] }, { "id": "PMID-10082134_E15", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1655, 1670 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_T11" } ] }, { "id": "PMID-10082134_E16", "type": "Positive_regulation", "trigger": { "text": [ "in response" ], "offsets": [ [ 1726, 1737 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E15" } ] }, { "id": "PMID-10082134_E17", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1752, 1761 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E15" } ] }, { "id": "PMID-10082134_E18", "type": "Positive_regulation", "trigger": { "text": [ "augmented" ], "offsets": [ [ 1806, 1815 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E15" } ] }, { "id": "PMID-10082134_E19", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1893, 1900 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E20" } ] }, { "id": "PMID-10082134_E20", "type": "Positive_regulation", "trigger": { "text": [ "directing" ], "offsets": [ [ 1918, 1927 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E21" } ] }, { "id": "PMID-10082134_E21", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1928, 1937 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E22" } ] }, { "id": "PMID-10082134_E22", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1938, 1948 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_T12" } ] }, { "id": "PMID-10082134_E23", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 2037, 2052 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_T13" } ] }, { "id": "PMID-10082134_E24", "type": "Positive_regulation", "trigger": { "text": [ "occurs" ], "offsets": [ [ 2064, 2070 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E23" } ] }, { "id": "PMID-10082134_E25", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 2146, 2154 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E26" } ] }, { "id": "PMID-10082134_E26", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 2185, 2193 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_E27" } ] }, { "id": "PMID-10082134_E27", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 2229, 2244 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082134_T14" } ] } ]

[]

[]

[ { "id": "PMID-10082473__text", "type": "abstract", "text": [ "Molecular mechanisms of neutrophil-endothelial cell adhesion induced by redox imbalance. \nPrevious studies have implicated a role for intracellular thiols in the activation of nuclear factor-kappaB and transcriptional regulation of endothelial cell adhesion molecules. This study was designed to determine whether changes in endothelial cell glutathione (GSH) or oxidized glutathione (GSSG) can alter neutrophil adhesivity and to define the molecular mechanism that underlies this GSSG/GSH-induced adhesion response. Treatment of human umbilical vein endothelial cell (HUVEC) monolayers for 6 hours with 0.2 mmol/L diamide and 1 mmol/L buthionine sulfoximine (BSO) decreased GSH levels and increased the ratio of GSSG to GSH without cell toxicity. These redox changes are similar to those observed with anoxia/reoxygenation. Diamide plus BSO-induced thiol/disulfide imbalance was associated with a biphasic increase in neutrophil adhesion to HUVECs with peak responses observed at 15 minutes (phase 1) and 240 minutes (phase 2). N-Acetylcysteine treatment attenuated neutrophil adhesion in both phases, which indicated a role for GSH in the adhesion responses. Interestingly, phase 1 adhesion was inversely correlated with GSH levels but not with the GSSG/GSH ratio, whereas phase 2 neutrophil adhesion was positively correlated with GSSG/GSH ratio but not with GSH levels. Intercellular adhesion molecule-1 and P-selectin-specific monoclonal antibodies attenuated the increased neutrophil adhesion during both phases, whereas an anti-E-selectin monoclonal antibody also attenuated the phase 2 response. Pretreatment with actinomycin D and cycloheximide or with competing ds-oligonucleotides that contained nuclear factor-kappaB or activator protein-1 cognate DNA sequences significantly attenuated the phase 2 response, which implicated a role for de novo protein synthesis. Surface expression of intercellular adhesion molecule-1, P-selectin, and E-selectin on HUVECs correlated with the phase 1 and 2 neutrophil adhesion responses. This study demonstrates that changes in endothelial cell GSSG/GSH cause transcription-independent and transcription-dependent surface expression of different endothelial cell adhesion molecules, which leads to a 2-phase neutrophil-endothelial adhesion response. " ], "offsets": [ [ 0, 2297 ] ] } ]

[ { "id": "PMID-10082473_T1", "type": "Protein", "text": [ "Intercellular adhesion molecule-1" ], "offsets": [ [ 1374, 1407 ] ], "normalized": [] }, { "id": "PMID-10082473_T2", "type": "Protein", "text": [ "P-selectin" ], "offsets": [ [ 1412, 1422 ] ], "normalized": [] }, { "id": "PMID-10082473_T3", "type": "Protein", "text": [ "E-selectin" ], "offsets": [ [ 1535, 1545 ] ], "normalized": [] }, { "id": "PMID-10082473_T4", "type": "Protein", "text": [ "intercellular adhesion molecule-1" ], "offsets": [ [ 1898, 1931 ] ], "normalized": [] }, { "id": "PMID-10082473_T5", "type": "Protein", "text": [ "P-selectin" ], "offsets": [ [ 1933, 1943 ] ], "normalized": [] }, { "id": "PMID-10082473_T6", "type": "Protein", "text": [ "E-selectin" ], "offsets": [ [ 1949, 1959 ] ], "normalized": [] } ]

[ { "id": "PMID-10082473_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1884, 1894 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082473_T4" } ] }, { "id": "PMID-10082473_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1884, 1894 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082473_T6" } ] }, { "id": "PMID-10082473_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1884, 1894 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10082473_T5" } ] } ]

[]

[]

[ { "id": "PMID-10087185__text", "type": "abstract", "text": [ "Decreased proteasome-mediated degradation in T cells from the elderly: A role in immune senescence. \nInduction of NFkappaB is a highly regulated process requiring phosphorylation, ubiquitination, and proteasome-mediated degradation of the cytosolic inhibitor IkappaBalpha. Analyses of the regulation of IkappaBalpha in TNF-alpha-treated T lymphocytes from young and elderly donors revealed severely compromised degradation of IkappaBalpha in T cells from the elderly. Examination of activation-induced phosphorylation and ubiquitination of IkappaBalpha did not demonstrate any significant age-related alterations. However, examination of proteasome activity in these T cells using fluorogenic peptide assays revealed a significant age-related decline in chymotryptic activity. These results suggest that a decline in proteasome activity results in a failure to fully degrade IkappaBalpha in the elderly. This failure to degrade IkappaBalpha may underlie both the observed decrease in NFkappaB induction and the IL-2 receptor expression in TNF-treated T cells during aging. Thus, decreased proteasome-mediated degradation may be central to immune dysfunction that accompanies aging. Copyright 1999 Academic Press. " ], "offsets": [ [ 0, 1213 ] ] } ]

[ { "id": "PMID-10087185_T1", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 259, 271 ] ], "normalized": [] }, { "id": "PMID-10087185_T2", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 303, 315 ] ], "normalized": [] }, { "id": "PMID-10087185_T3", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 319, 328 ] ], "normalized": [] }, { "id": "PMID-10087185_T4", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 426, 438 ] ], "normalized": [] }, { "id": "PMID-10087185_T5", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 540, 552 ] ], "normalized": [] }, { "id": "PMID-10087185_T6", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 875, 887 ] ], "normalized": [] }, { "id": "PMID-10087185_T7", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 928, 940 ] ], "normalized": [] } ]

[ { "id": "PMID-10087185_E1", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 211, 219 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087185_E2" } ] }, { "id": "PMID-10087185_E2", "type": "Protein_catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 220, 231 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087185_T1" } ] }, { "id": "PMID-10087185_E3", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 289, 299 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087185_T2" } ] }, { "id": "PMID-10087185_E4", "type": "Protein_catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 411, 422 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087185_T4" } ] }, { "id": "PMID-10087185_E5", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 494, 501 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087185_E6" } ] }, { "id": "PMID-10087185_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 502, 517 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087185_T5" } ] }, { "id": "PMID-10087185_E7", "type": "Regulation", "trigger": { "text": [ "alterations" ], "offsets": [ [ 601, 612 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087185_E5" } ] }, { "id": "PMID-10087185_E8", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 837, 844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087185_E9" } ] }, { "id": "PMID-10087185_E9", "type": "Protein_catabolism", "trigger": { "text": [ "degrade" ], "offsets": [ [ 867, 874 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087185_T6" } ] }, { "id": "PMID-10087185_E10", "type": "Protein_catabolism", "trigger": { "text": [ "degrade" ], "offsets": [ [ 920, 927 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087185_T7" } ] } ]

[]

[]

[ { "id": "PMID-10087993__text", "type": "abstract", "text": [ "Identification of upstream regulatory elements that repress expression of adult beta-like globin genes in a primitive erythroid environment. \nOur investigations have focused on localizing cis-elements responsible for the down regulation of the adult beta-like globin genes (delta and beta) in immature, or primitive erythroid tissues. We studied their activity after transfection into K562 cells, an erythroleukemia cell line with an embryonic-fetal phenotype. Analyzed DNA sequences included delta and beta 5' flanking regions extending from approximately -500 to +50bp (promoter regions), truncated delta and beta 5' flanking regions extending from approximately -250 to +50 bp, and chimeric promoter constructions, which consisted of a distal delta or beta fragment fused to a proximal beta or delta sequence. In CAT reporter constructions no appreciable level of CAT activity was supported by the beta globin promoter, and only low level activity by the delta promoter. Truncation of the beta globin promoter led to a 2-3 fold increase in promoter activity. In contrast, deletion of the upstream portion of the delta promoter led to a 10 fold decrease in expression. Coupling of the upstream beta globin sequence from approximately -500 to -250 bp to the truncated delta promoter fragment led to complete extinction of transcription activity, consistent with a negative regulatory effect of the beta globin gene upstream element(s). Fusion of the upstream portion of the delta promoter to the truncated beta globin promoter yielded a modest increase in promoter strength relative to the truncated beta gene promoter, indicating the presence of a positive transcriptional element(s) in the upstream delta globin regulatory region. Site-directed mutagenesis of binding sites for the repressor proteins BP1 and BP2 in the upstream portion of the beta globin gene flanking region led to a 4-6 fold increase in promoter activity. DNase I footprinting of the upstream delta-globin region revealed protected sequences corresponding to consensus binding sites for GATA-1 and BP2. These results confirm that sequences in the upstream promoter region of the adult beta globin gene contribute to its factor-mediated suppression early in development and then may modulate its expression at a later stage. " ], "offsets": [ [ 0, 2297 ] ] } ]

[ { "id": "PMID-10087993_T1", "type": "Protein", "text": [ "delta" ], "offsets": [ [ 274, 279 ] ], "normalized": [] }, { "id": "PMID-10087993_T2", "type": "Protein", "text": [ "beta" ], "offsets": [ [ 284, 288 ] ], "normalized": [] }, { "id": "PMID-10087993_T3", "type": "Protein", "text": [ "delta" ], "offsets": [ [ 493, 498 ] ], "normalized": [] }, { "id": "PMID-10087993_T4", "type": "Protein", "text": [ "beta" ], "offsets": [ [ 503, 507 ] ], "normalized": [] }, { "id": "PMID-10087993_T5", "type": "Protein", "text": [ "delta" ], "offsets": [ [ 601, 606 ] ], "normalized": [] }, { "id": "PMID-10087993_T6", "type": "Protein", "text": [ "beta" ], "offsets": [ [ 611, 615 ] ], "normalized": [] }, { "id": "PMID-10087993_T7", "type": "Protein", "text": [ "delta" ], "offsets": [ [ 746, 751 ] ], "normalized": [] }, { "id": "PMID-10087993_T8", "type": "Protein", "text": [ "beta" ], "offsets": [ [ 755, 759 ] ], "normalized": [] }, { "id": "PMID-10087993_T9", "type": "Protein", "text": [ "beta" ], "offsets": [ [ 789, 793 ] ], "normalized": [] }, { "id": "PMID-10087993_T10", "type": "Protein", "text": [ "delta" ], "offsets": [ [ 797, 802 ] ], "normalized": [] }, { "id": "PMID-10087993_T11", "type": "Protein", "text": [ "CAT" ], "offsets": [ [ 816, 819 ] ], "normalized": [] }, { "id": "PMID-10087993_T12", "type": "Protein", "text": [ "CAT" ], "offsets": [ [ 867, 870 ] ], "normalized": [] }, { "id": "PMID-10087993_T13", "type": "Protein", "text": [ "beta globin" ], "offsets": [ [ 901, 912 ] ], "normalized": [] }, { "id": "PMID-10087993_T14", "type": "Protein", "text": [ "delta" ], "offsets": [ [ 958, 963 ] ], "normalized": [] }, { "id": "PMID-10087993_T15", "type": "Protein", "text": [ "beta globin" ], "offsets": [ [ 992, 1003 ] ], "normalized": [] }, { "id": "PMID-10087993_T16", "type": "Protein", "text": [ "delta" ], "offsets": [ [ 1115, 1120 ] ], "normalized": [] }, { "id": "PMID-10087993_T17", "type": "Protein", "text": [ "beta globin" ], "offsets": [ [ 1196, 1207 ] ], "normalized": [] }, { "id": "PMID-10087993_T18", "type": "Protein", "text": [ "delta" ], "offsets": [ [ 1269, 1274 ] ], "normalized": [] }, { "id": "PMID-10087993_T19", "type": "Protein", "text": [ "beta globin" ], "offsets": [ [ 1399, 1410 ] ], "normalized": [] }, { "id": "PMID-10087993_T20", "type": "Protein", "text": [ "delta" ], "offsets": [ [ 1475, 1480 ] ], "normalized": [] }, { "id": "PMID-10087993_T21", "type": "Protein", "text": [ "beta globin" ], "offsets": [ [ 1507, 1518 ] ], "normalized": [] }, { "id": "PMID-10087993_T22", "type": "Protein", "text": [ "beta" ], "offsets": [ [ 1601, 1605 ] ], "normalized": [] }, { "id": "PMID-10087993_T23", "type": "Protein", "text": [ "delta globi" ], "offsets": [ [ 1702, 1713 ] ], "normalized": [] }, { "id": "PMID-10087993_T24", "type": "Protein", "text": [ "BP1" ], "offsets": [ [ 1804, 1807 ] ], "normalized": [] }, { "id": "PMID-10087993_T25", "type": "Protein", "text": [ "BP2" ], "offsets": [ [ 1812, 1815 ] ], "normalized": [] }, { "id": "PMID-10087993_T26", "type": "Protein", "text": [ "beta globin" ], "offsets": [ [ 1847, 1858 ] ], "normalized": [] }, { "id": "PMID-10087993_T27", "type": "Protein", "text": [ "DNase I" ], "offsets": [ [ 1929, 1936 ] ], "normalized": [] }, { "id": "PMID-10087993_T28", "type": "Protein", "text": [ "delta-globin" ], "offsets": [ [ 1966, 1978 ] ], "normalized": [] }, { "id": "PMID-10087993_T29", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 2060, 2066 ] ], "normalized": [] }, { "id": "PMID-10087993_T30", "type": "Protein", "text": [ "BP2" ], "offsets": [ [ 2071, 2074 ] ], "normalized": [] }, { "id": "PMID-10087993_T31", "type": "Protein", "text": [ "beta globin" ], "offsets": [ [ 2158, 2169 ] ], "normalized": [] }, { "id": "PMID-10087993_T35", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 913, 921 ] ], "normalized": [] }, { "id": "PMID-10087993_T36", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 964, 972 ] ], "normalized": [] }, { "id": "PMID-10087993_T37", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1004, 1012 ] ], "normalized": [] }, { "id": "PMID-10087993_T41", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1519, 1527 ] ], "normalized": [] }, { "id": "PMID-10087993_T43", "type": "Entity", "text": [ "upstream promoter region" ], "offsets": [ [ 2120, 2144 ] ], "normalized": [] } ]

[ { "id": "PMID-10087993_E1", "type": "Regulation", "trigger": { "text": [ "responsible" ], "offsets": [ [ 201, 212 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087993_E4" } ] }, { "id": "PMID-10087993_E2", "type": "Regulation", "trigger": { "text": [ "responsible" ], "offsets": [ [ 201, 212 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087993_E3" } ] }, { "id": "PMID-10087993_E3", "type": "Negative_regulation", "trigger": { "text": [ "down regulation" ], "offsets": [ [ 221, 236 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087993_T2" } ] }, { "id": "PMID-10087993_E4", "type": "Negative_regulation", "trigger": { "text": [ "down regulation" ], "offsets": [ [ 221, 236 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087993_T1" } ] }, { "id": "PMID-10087993_E5", "type": "Positive_regulation", "trigger": { "text": [ "supported" ], "offsets": [ [ 884, 893 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087993_T12" }, { "role": "Cause", "ref_id": "PMID-10087993_T14" }, { "role": "CSite", "ref_id": "PMID-10087993_T36" } ] }, { "id": "PMID-10087993_E6", "type": "Positive_regulation", "trigger": { "text": [ "supported" ], "offsets": [ [ 884, 893 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087993_T12" }, { "role": "Cause", "ref_id": "PMID-10087993_T13" }, { "role": "CSite", "ref_id": "PMID-10087993_T35" } ] }, { "id": "PMID-10087993_E7", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 1031, 1039 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087993_T15" }, { "role": "Site", "ref_id": "PMID-10087993_T37" } ] }, { "id": "PMID-10087993_E8", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 1147, 1155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087993_E9" } ] }, { "id": "PMID-10087993_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1159, 1169 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087993_T12" } ] }, { "id": "PMID-10087993_E10", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 1545, 1553 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087993_T21" }, { "role": "Site", "ref_id": "PMID-10087993_T41" } ] }, { "id": "PMID-10087993_E11", "type": "Positive_regulation", "trigger": { "text": [ "contribute" ], "offsets": [ [ 2175, 2185 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087993_E12" }, { "role": "Cause", "ref_id": "PMID-10087993_T31" }, { "role": "CSite", "ref_id": "PMID-10087993_T43" } ] }, { "id": "PMID-10087993_E12", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 2209, 2220 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087993_T31" } ] }, { "id": "PMID-10087993_E13", "type": "Regulation", "trigger": { "text": [ "modulate" ], "offsets": [ [ 2255, 2263 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087993_E14" }, { "role": "Cause", "ref_id": "PMID-10087993_E11" } ] }, { "id": "PMID-10087993_E14", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2268, 2278 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10087993_T31" } ] } ]

[]

[]

[ { "id": "PMID-10089140__text", "type": "abstract", "text": [ "Reduction of tumour necrosis factor alpha expression and signalling in peripheral blood mononuclear cells from patients with thalassaemia or sickle cell anaemia upon treatment with desferrioxamine. \nRecent evidence indicates that the rate of progression of the HIV-1 disease is significantly reduced in thalassaemia major patients upon treatment with high doses of desferrioxamine (DFX). The authors have previously demonstrated that in vitro exposure of mononuclear cells to DFX decreases the bioavailability of tumour necrosis factor alpha (TNF-alpha) which has a stimulatory effect on HIV-1 replication. In this study, therefore, TNF-alpha bioavailability from mononuclear cells isolated from 10 patients with thalassaemia or sickle cell anaemia given DFX as compared to 10 untreated subjects has been evaluated. Evidence is presented showing that DFX treatment reduces TNF-alpha bioavailability (P<0.05) by inhibiting its steady state (P<0.05) and by enhancing its inactivation through binding to soluble TNF-alpha receptor type II (P<0.05). We also show that DFX treatment limits the in vivo activation of NF-kappaB, a transcription factor involved in both TNF-alpha gene transcription and TNF-alpha signalling (P<0.005). We conclude that TNF-alpha bioavailability and signalling are impaired in patients upon DFX treatment. This mechanism may contribute to delayed progression of the HIV-1 infection in vivo. Copyright 1999 Academic Press. " ], "offsets": [ [ 0, 1446 ] ] } ]

[ { "id": "PMID-10089140_T1", "type": "Protein", "text": [ "tumour necrosis factor alpha" ], "offsets": [ [ 13, 41 ] ], "normalized": [] }, { "id": "PMID-10089140_T2", "type": "Protein", "text": [ "tumour necrosis factor alpha" ], "offsets": [ [ 513, 541 ] ], "normalized": [] }, { "id": "PMID-10089140_T3", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 543, 552 ] ], "normalized": [] }, { "id": "PMID-10089140_T4", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 633, 642 ] ], "normalized": [] }, { "id": "PMID-10089140_T5", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 873, 882 ] ], "normalized": [] }, { "id": "PMID-10089140_T6", "type": "Protein", "text": [ "TNF-alpha receptor type II" ], "offsets": [ [ 1009, 1035 ] ], "normalized": [] }, { "id": "PMID-10089140_T7", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1162, 1171 ] ], "normalized": [] }, { "id": "PMID-10089140_T8", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1195, 1204 ] ], "normalized": [] }, { "id": "PMID-10089140_T9", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1244, 1253 ] ], "normalized": [] } ]

[ { "id": "PMID-10089140_E1", "type": "Negative_regulation", "trigger": { "text": [ "Reduction" ], "offsets": [ [ 0, 9 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10089140_E2" } ] }, { "id": "PMID-10089140_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 42, 52 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10089140_T1" } ] }, { "id": "PMID-10089140_E3", "type": "Negative_regulation", "trigger": { "text": [ "decreases" ], "offsets": [ [ 480, 489 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10089140_T3" } ] }, { "id": "PMID-10089140_E4", "type": "Negative_regulation", "trigger": { "text": [ "reduces" ], "offsets": [ [ 865, 872 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10089140_T5" } ] }, { "id": "PMID-10089140_E5", "type": "Positive_regulation", "trigger": { "text": [ "enhancing" ], "offsets": [ [ 955, 964 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10089140_E6" }, { "role": "Cause", "ref_id": "PMID-10089140_E7" } ] }, { "id": "PMID-10089140_E6", "type": "Negative_regulation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 969, 981 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10089140_T6" } ] }, { "id": "PMID-10089140_E7", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 990, 997 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10089140_T6" } ] }, { "id": "PMID-10089140_E8", "type": "Positive_regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 1145, 1153 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10089140_E9" } ] }, { "id": "PMID-10089140_E9", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1177, 1190 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10089140_T7" } ] }, { "id": "PMID-10089140_E10", "type": "Negative_regulation", "trigger": { "text": [ "impaired" ], "offsets": [ [ 1289, 1297 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10089140_T9" } ] } ]

[ { "id": "PMID-10089140_1", "entity_ids": [ "PMID-10089140_T3", "PMID-10089140_T2" ] } ]

[]

[ { "id": "PMID-10101034__text", "type": "abstract", "text": [ "Inhibition of cyclooxygenase-2 expression by 4-trifluoromethyl derivatives of salicylate, triflusal, and its deacetylated metabolite, 2-hydroxy-4-trifluoromethylbenzoic acid. \nThe therapeutic potential of drugs that block the induction of cyclooxygenase-2 has been emphasized. When two 4-trifluoromethyl salicylate derivatives [2-acetoxy-4-trifluoromethyl-benzoic acid (triflusal) and its deacetylated metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB)] were compared with aspirin and sodium salicylate as cyclooxygenase-2 (COX-2) inhibitors, we observed that in bacterial lipopolysaccharide-activated human blood, triflusal, aspirin, and HTB, but not sodium salicylate, inhibited COX-2-mediated prostaglandin E2 (PGE2) production (IC50 = 0.16, 0.18, 0.39, and >10 mM, respectively). However, only triflusal and aspirin inhibited purified COX-2 enzyme. To test this apparent discrepancy, we realized that HTB and triflusal (but neither aspirin nor salicylate) produced a concentration-dependent inhibition of COX-2 protein expression in peripheral human mononuclear cells. This observation was further confirmed in a rat air pouch model in vivo, in which both aspirin and triflusal inhibited PGE2 production (ID50 = 18.9 and 11.4 mg/kg p.o., respectively) but only triflusal-treated animals showed a decrease in COX-2 expression. This different behavior may be, at least in part, due to the ability of HTB and triflusal to block the activation of the transcription factor nuclear factor-kappaB to a higher extent than aspirin and sodium salicylate. Thus, in addition to inhibiting the COX-2 activity at therapeutic concentrations, triflusal is able to block through its metabolite HTB the expression of new enzyme, and hence the resumption of PGE2 synthesis. Triflusal and HTB may exert beneficial effects in processes in which de novo COX-2 expression is involved and, in a broader sense, in pathological situations in which genes under nuclear factor-kappaB control are up-regulated. " ], "offsets": [ [ 0, 1992 ] ] } ]

[ { "id": "PMID-10101034_T1", "type": "Protein", "text": [ "cyclooxygenase-2" ], "offsets": [ [ 14, 30 ] ], "normalized": [] }, { "id": "PMID-10101034_T2", "type": "Protein", "text": [ "cyclooxygenase-2" ], "offsets": [ [ 239, 255 ] ], "normalized": [] }, { "id": "PMID-10101034_T3", "type": "Protein", "text": [ "cyclooxygenase-2" ], "offsets": [ [ 512, 528 ] ], "normalized": [] }, { "id": "PMID-10101034_T4", "type": "Protein", "text": [ "COX-2" ], "offsets": [ [ 530, 535 ] ], "normalized": [] }, { "id": "PMID-10101034_T5", "type": "Protein", "text": [ "COX-2" ], "offsets": [ [ 687, 692 ] ], "normalized": [] }, { "id": "PMID-10101034_T6", "type": "Protein", "text": [ "COX-2" ], "offsets": [ [ 845, 850 ] ], "normalized": [] }, { "id": "PMID-10101034_T7", "type": "Protein", "text": [ "COX-2" ], "offsets": [ [ 1015, 1020 ] ], "normalized": [] }, { "id": "PMID-10101034_T8", "type": "Protein", "text": [ "COX-2" ], "offsets": [ [ 1318, 1323 ] ], "normalized": [] }, { "id": "PMID-10101034_T9", "type": "Protein", "text": [ "COX-2" ], "offsets": [ [ 1591, 1596 ] ], "normalized": [] }, { "id": "PMID-10101034_T10", "type": "Protein", "text": [ "COX-2" ], "offsets": [ [ 1842, 1847 ] ], "normalized": [] } ]

[ { "id": "PMID-10101034_E1", "type": "Negative_regulation", "trigger": { "text": [ "Inhibition" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10101034_E2" } ] }, { "id": "PMID-10101034_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 31, 41 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10101034_T1" } ] }, { "id": "PMID-10101034_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 826, 835 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10101034_T6" } ] }, { "id": "PMID-10101034_E4", "type": "Positive_regulation", "trigger": { "text": [ "produced" ], "offsets": [ [ 966, 974 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10101034_E5" } ] }, { "id": "PMID-10101034_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1001, 1011 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10101034_E6" } ] }, { "id": "PMID-10101034_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1029, 1039 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10101034_T7" } ] }, { "id": "PMID-10101034_E7", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 1306, 1314 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10101034_E8" } ] }, { "id": "PMID-10101034_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1324, 1334 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10101034_T8" } ] }, { "id": "PMID-10101034_E9", "type": "Negative_regulation", "trigger": { "text": [ "block" ], "offsets": [ [ 1658, 1663 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10101034_E10" } ] }, { "id": "PMID-10101034_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1695, 1705 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10101034_T8" } ] }, { "id": "PMID-10101034_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1848, 1858 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10101034_T10" } ] } ]

[ { "id": "PMID-10101034_1", "entity_ids": [ "PMID-10101034_T3", "PMID-10101034_T4" ] } ]

[]

[ { "id": "PMID-10102628__text", "type": "abstract", "text": [ "Expression of IkappaBalpha in the nucleus of human peripheral blood T lymphocytes. \nAccording to current models the inhibitory capacity of I(kappa)B(alpha) would be mediated through the retention of Rel/NF-kappaB proteins in the cytosol. However, I(kappa)B(alpha) has also been detected in the nucleus of cell lines and when overexpressed by transient transfection. To gain better insight into the potential role of nuclear I(kappa)B(alpha) in a physiological context we have analysed its presence in the nucleus of human peripheral blood T lymphocytes (PBL). We demonstrate the nuclear localization of I(kappa)B(alpha) in PBL by different techniques: Western blot, indirect immunofluorescence and electron microscopy. Low levels of nuclear I(kappa)B(alpha) were detected in resting cells whereas a superinduction was obtained after PMA activation. The nuclear pool of I(kappa)B(alpha) showed a higher stability than cytosolic I(kappa)B(alpha) and was partially independent of the resynthesis of the protein. Unexpectedly, the presence of nuclear I(kappa)B(alpha) did not inhibit NF-kappaB binding to DNA and this phenomenon was not due to the presence of IkappaBbeta at the nuclear level. Immunoprecipitation experiments failed to demonstrate an association between nuclear I(kappa)B(alpha) and NF-kappaB proteins. Our results demonstrate that in resting and PMA-activated human PBL, I(kappa)B(alpha) is present in the nucleus in an apparently inactive form unable to disrupt NF-kappaB binding from DNA. " ], "offsets": [ [ 0, 1505 ] ] } ]

[ { "id": "PMID-10102628_T1", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 14, 26 ] ], "normalized": [] }, { "id": "PMID-10102628_T2", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 139, 155 ] ], "normalized": [] }, { "id": "PMID-10102628_T3", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 247, 263 ] ], "normalized": [] }, { "id": "PMID-10102628_T4", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 424, 440 ] ], "normalized": [] }, { "id": "PMID-10102628_T5", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 603, 619 ] ], "normalized": [] }, { "id": "PMID-10102628_T6", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 741, 757 ] ], "normalized": [] }, { "id": "PMID-10102628_T7", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 869, 885 ] ], "normalized": [] }, { "id": "PMID-10102628_T8", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 927, 943 ] ], "normalized": [] }, { "id": "PMID-10102628_T9", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 1047, 1063 ] ], "normalized": [] }, { "id": "PMID-10102628_T10", "type": "Protein", "text": [ "IkappaBbeta" ], "offsets": [ [ 1156, 1167 ] ], "normalized": [] }, { "id": "PMID-10102628_T11", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 1275, 1291 ] ], "normalized": [] }, { "id": "PMID-10102628_T12", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 1385, 1401 ] ], "normalized": [] }, { "id": "PMID-10102628_T19", "type": "Entity", "text": [ "nuclear" ], "offsets": [ [ 579, 586 ] ], "normalized": [] }, { "id": "PMID-10102628_T27", "type": "Entity", "text": [ "nuclear" ], "offsets": [ [ 1039, 1046 ] ], "normalized": [] }, { "id": "PMID-10102628_T30", "type": "Entity", "text": [ "nuclear" ], "offsets": [ [ 1175, 1182 ] ], "normalized": [] }, { "id": "PMID-10102628_T32", "type": "Entity", "text": [ "nucleus" ], "offsets": [ [ 1420, 1427 ] ], "normalized": [] } ]

[ { "id": "PMID-10102628_E1", "type": "Gene_expression", "trigger": { "text": [ "Expression" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_T1" } ] }, { "id": "PMID-10102628_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory capacity" ], "offsets": [ [ 116, 135 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_T2" } ] }, { "id": "PMID-10102628_E3", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 165, 173 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_E2" } ] }, { "id": "PMID-10102628_E4", "type": "Positive_regulation", "trigger": { "text": [ "detected" ], "offsets": [ [ 278, 286 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_E5" }, { "role": "Cause", "ref_id": "PMID-10102628_E6" } ] }, { "id": "PMID-10102628_E5", "type": "Gene_expression", "trigger": { "text": [ "detected" ], "offsets": [ [ 278, 286 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_T3" } ] }, { "id": "PMID-10102628_E6", "type": "Positive_regulation", "trigger": { "text": [ "overexpressed" ], "offsets": [ [ 325, 338 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_T3" } ] }, { "id": "PMID-10102628_E7", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 587, 599 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_T5" }, { "role": "ToLoc", "ref_id": "PMID-10102628_T19" } ] }, { "id": "PMID-10102628_E8", "type": "Positive_regulation", "trigger": { "text": [ "detected" ], "offsets": [ [ 763, 771 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_T6" } ] }, { "id": "PMID-10102628_E9", "type": "Positive_regulation", "trigger": { "text": [ "super" ], "offsets": [ [ 799, 804 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_E10" } ] }, { "id": "PMID-10102628_E10", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 804, 813 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_T6" } ] }, { "id": "PMID-10102628_E11", "type": "Positive_regulation", "trigger": { "text": [ "higher stability" ], "offsets": [ [ 895, 911 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_T7" } ] }, { "id": "PMID-10102628_E12", "type": "Gene_expression", "trigger": { "text": [ "resynthesis" ], "offsets": [ [ 981, 992 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_T7" } ] }, { "id": "PMID-10102628_E13", "type": "Localization", "trigger": { "text": [ "presence" ], "offsets": [ [ 1027, 1035 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_T9" }, { "role": "AtLoc", "ref_id": "PMID-10102628_T27" } ] }, { "id": "PMID-10102628_E14", "type": "Regulation", "trigger": { "text": [ "presence" ], "offsets": [ [ 1144, 1152 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_E13" }, { "role": "Cause", "ref_id": "PMID-10102628_E15" } ] }, { "id": "PMID-10102628_E15", "type": "Localization", "trigger": { "text": [ "presence" ], "offsets": [ [ 1144, 1152 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_T10" }, { "role": "AtLoc", "ref_id": "PMID-10102628_T30" } ] }, { "id": "PMID-10102628_E16", "type": "Localization", "trigger": { "text": [ "present" ], "offsets": [ [ 1405, 1412 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10102628_T12" }, { "role": "AtLoc", "ref_id": "PMID-10102628_T32" } ] } ]

[]

[]

[ { "id": "PMID-10102791__text", "type": "abstract", "text": [ "PGG-glucan, a soluble beta-(1,3)-glucan, enhances the oxidative burst response, microbicidal activity, and activates an NF-kappa B-like factor in human PMN: evidence for a glycosphingolipid beta-(1,3)-glucan receptor. \nPGG-Glucan, a soluble beta-(1,6)-branched beta-(1,3)-linked glucose homopolymer derived from the cell wall of the yeast Saccharomyces cerevisiae, is an immunomodulator which enhances leukocyte anti-infective activity and enhances myeloid and megakaryocyte progenitor proliferation. Incubation of human whole blood with PGG-Glucan significantly enhanced the oxidative burst response of subsequently isolated blood leukocytes to both soluble and particulate activators in a dose-dependent manner, and increased leukocyte microbicidal activity. No evidence for inflammatory cytokine production was obtained under these conditions. Electrophoretic mobility shift assays demonstrated that PGG-Glucan induced the activation of an NF-kappaB-like nuclear transcription factor in purified human neutrophils. The binding of 3H-PGG-Glucan to human leukocyte membranes was specific, concentration-dependent, saturable, and high affinity (Kd approximately 6 nM). A monoclonal antibody specific to the glycosphingolipid lactosylceramide was able to inhibit activation of the NF-kappaB-like factor by PGG-Glucan, and ligand binding data, including polysaccharide specificity, suggested that the PGG-Glucan binding moiety was lactosylceramide. These results indicate that PGG-Glucan enhances neutrophil anti-microbial functions and that interaction between this beta-glucan and human neutrophils is mediated by the glycosphingolipid lactosylceramide present at the cell surface. " ], "offsets": [ [ 0, 1682 ] ] } ]

[]

[]

[]

[]

[ { "id": "PMID-10191934__text", "type": "abstract", "text": [ "[Corticoids and allergy] \nInflammation is constantly observed in allergic reactions. Corticosteroids are most effective in preventing the late phase of allergic reaction. The action of glucocorticosteroids is mediated through glucocorticoid receptors present in the cellular cytoplasm. When activated, glucocorticoid receptors form a dimer and bind to DNA after migration into the nucleus. Interaction to DNA induces changes in the transcription rate, leading to either gene induction or gene repression. Glucocorticoid receptors are also able to interact with transcriptional factors such as AP-1 (activator protein-1) of NF-kappa B (nuclear factor-kappa B). Through these actions glucocorticosteroids are susceptible to modify functions of cells involved in the allergic inflammatory response. They are in particular able to inhibit most of the pro-inflammatory functions of the eosinophils. " ], "offsets": [ [ 0, 894 ] ] } ]

[]

[]

[]

[]

[ { "id": "PMID-10194184__text", "type": "abstract", "text": [ "Activation of NF-kappaB in Mycobacterium tuberculosis- induced interleukin-2 receptor expression in mononuclear phagocytes. \nSoluble interleukin-2 receptor-alpha (IL-2Ralpha) has been reported to be increased in the sera of patients with advanced tuberculosis, and levels decline after therapy in accordance with improvement of radiologic findings. We investigated expression of the IL-2Ralpha in bronchoalveolar lavage (BAL) cells in active pulmonary tuberculosis, and evaluated the mechanism Mycobacterium tuberculosis induces in the IL-2Ralpha using the THP-1 mononuclear phagocyte cell line. We found IL-2Ralpha expression to be increased in BAL cells from involved sites of active pulmonary tuberculosis. Expression of the alpha-chain of IL-2Ralpha on peripheral blood monocytes (PBM) was induced by M. tuberculosis by flow cytometry evaluation. Northern analysis demonstrated increased IL-2Ralpha gene expression after stimulation with M. tuberculosis which was further induced by interferon-gamma (IFN-gamma). The IL-2Ralpha promoter containing the nuclear factor kappa B (NF-kappaB) site was transcriptionally induced by M. tuberculosis and this NF-kappaB site could confer inducibility to a heterologous herpes thymidine kinase (TK) promoter by M. tuberculosis. Electrophoretic mobility shift assays (EMSAs) revealed specific binding of nuclear protein to the NF-kappaB site upon induction with M. tuberculosis. Using antibodies against the p50 and p65 subunits of NF-kappaB in EMSAs, the involvement of both p50 and p65 proteins was further demonstrated. Functional expression of the IL-2Ralpha on mononuclear phagocytes in M. tuberculosis infection may play an important immunomodulatory role in the host response. " ], "offsets": [ [ 0, 1726 ] ] } ]

[ { "id": "PMID-10194184_T1", "type": "Protein", "text": [ "interleukin-2 receptor-alpha" ], "offsets": [ [ 133, 161 ] ], "normalized": [] }, { "id": "PMID-10194184_T2", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 163, 173 ] ], "normalized": [] }, { "id": "PMID-10194184_T3", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 383, 393 ] ], "normalized": [] }, { "id": "PMID-10194184_T4", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 536, 546 ] ], "normalized": [] }, { "id": "PMID-10194184_T5", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 605, 615 ] ], "normalized": [] }, { "id": "PMID-10194184_T6", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 743, 753 ] ], "normalized": [] }, { "id": "PMID-10194184_T7", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 892, 902 ] ], "normalized": [] }, { "id": "PMID-10194184_T8", "type": "Protein", "text": [ "interferon-gamma" ], "offsets": [ [ 987, 1003 ] ], "normalized": [] }, { "id": "PMID-10194184_T9", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1005, 1014 ] ], "normalized": [] }, { "id": "PMID-10194184_T10", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 1021, 1031 ] ], "normalized": [] }, { "id": "PMID-10194184_T11", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1450, 1453 ] ], "normalized": [] }, { "id": "PMID-10194184_T12", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1458, 1461 ] ], "normalized": [] }, { "id": "PMID-10194184_T13", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1518, 1521 ] ], "normalized": [] }, { "id": "PMID-10194184_T14", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1526, 1529 ] ], "normalized": [] }, { "id": "PMID-10194184_T15", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 1594, 1604 ] ], "normalized": [] }, { "id": "PMID-10194184_T27", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1032, 1040 ] ], "normalized": [] } ]

[ { "id": "PMID-10194184_E1", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 199, 208 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194184_T2" } ] }, { "id": "PMID-10194184_E2", "type": "Negative_regulation", "trigger": { "text": [ "decline" ], "offsets": [ [ 272, 279 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194184_E1" } ] }, { "id": "PMID-10194184_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 365, 375 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194184_T3" } ] }, { "id": "PMID-10194184_E4", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 521, 528 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194184_T4" } ] }, { "id": "PMID-10194184_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 616, 626 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194184_T5" } ] }, { "id": "PMID-10194184_E6", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 633, 642 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194184_E5" } ] }, { "id": "PMID-10194184_E7", "type": "Gene_expression", "trigger": { "text": [ "Expression" ], "offsets": [ [ 710, 720 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194184_T6" } ] }, { "id": "PMID-10194184_E8", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 794, 801 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194184_E7" } ] }, { "id": "PMID-10194184_E9", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 882, 891 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194184_E10" } ] }, { "id": "PMID-10194184_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 908, 918 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194184_T7" } ] }, { "id": "PMID-10194184_E11", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 976, 983 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194184_E10" }, { "role": "Cause", "ref_id": "PMID-10194184_T9" } ] }, { "id": "PMID-10194184_E12", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1118, 1125 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194184_T10" }, { "role": "Site", "ref_id": "PMID-10194184_T27" } ] }, { "id": "PMID-10194184_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1576, 1586 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194184_T15" } ] } ]

[ { "id": "PMID-10194184_1", "entity_ids": [ "PMID-10194184_T2", "PMID-10194184_T1" ] }, { "id": "PMID-10194184_2", "entity_ids": [ "PMID-10194184_T9", "PMID-10194184_T8" ] } ]

[]

[ { "id": "PMID-10194443__text", "type": "abstract", "text": [ "Regulation of the megakaryocytic glycoprotein IX promoter by the oncogenic Ets transcription factor Fli-1. \nGlycoprotein (GP) IX is a subunit of the von Willebrand receptor, GPIb-V-IX, which mediates adhesion of platelets to the subendothelium of damaged blood vessels. Previous characterization of the GPIX promoter identified a functional Ets site that, when disrupted, reduced promoter activity. However, the Ets protein(s) that regulated GPIX promoter expression was unknown. In this study, transient cotransfection of several GPIX promoter/reporter constructs into 293T kidney fibroblasts with a Fli-1 expression vector shows that the oncogenic protein Fli-1 can transactivate the GPIX promoter when an intact GPIX Ets site is present. In addition, Fli-1 binding of the GPIX Ets site was identified in antibody supershift experiments in nuclear extracts derived from hematopoietic human erythroleukemia cells. Comparative studies showed that Fli-1 was also able to transactivate the GPIbalpha and, to a lesser extent, the GPIIb promoter. Immunoblot analysis identified Fli-1 protein in lysates derived from platelets. In addition, expression of Fli-1 was identified immunohistochemically in megakaryocytes derived from CD34(+) cells treated with the megakaryocyte differentiation and proliferation factor, thrombopoietin. These results suggest that Fli-1 is likely to regulate lineage-specific genes during megakaryocytopoiesis. " ], "offsets": [ [ 0, 1434 ] ] } ]

[ { "id": "PMID-10194443_T1", "type": "Protein", "text": [ "glycoprotein IX" ], "offsets": [ [ 33, 48 ] ], "normalized": [] }, { "id": "PMID-10194443_T2", "type": "Protein", "text": [ "Fli-1" ], "offsets": [ [ 100, 105 ] ], "normalized": [] }, { "id": "PMID-10194443_T3", "type": "Protein", "text": [ "Glycoprotein (GP) IX" ], "offsets": [ [ 108, 128 ] ], "normalized": [] }, { "id": "PMID-10194443_T4", "type": "Protein", "text": [ "GPIX" ], "offsets": [ [ 303, 307 ] ], "normalized": [] }, { "id": "PMID-10194443_T5", "type": "Protein", "text": [ "GPIX" ], "offsets": [ [ 442, 446 ] ], "normalized": [] }, { "id": "PMID-10194443_T6", "type": "Protein", "text": [ "GPIX" ], "offsets": [ [ 531, 535 ] ], "normalized": [] }, { "id": "PMID-10194443_T7", "type": "Protein", "text": [ "Fli-1" ], "offsets": [ [ 601, 606 ] ], "normalized": [] }, { "id": "PMID-10194443_T8", "type": "Protein", "text": [ "Fli-1" ], "offsets": [ [ 658, 663 ] ], "normalized": [] }, { "id": "PMID-10194443_T9", "type": "Protein", "text": [ "GPIX" ], "offsets": [ [ 686, 690 ] ], "normalized": [] }, { "id": "PMID-10194443_T10", "type": "Protein", "text": [ "GPIX" ], "offsets": [ [ 715, 719 ] ], "normalized": [] }, { "id": "PMID-10194443_T11", "type": "Protein", "text": [ "Fli-1" ], "offsets": [ [ 754, 759 ] ], "normalized": [] }, { "id": "PMID-10194443_T12", "type": "Protein", "text": [ "GPIX" ], "offsets": [ [ 775, 779 ] ], "normalized": [] }, { "id": "PMID-10194443_T13", "type": "Protein", "text": [ "Fli-1" ], "offsets": [ [ 947, 952 ] ], "normalized": [] }, { "id": "PMID-10194443_T14", "type": "Protein", "text": [ "GPIbalpha" ], "offsets": [ [ 988, 997 ] ], "normalized": [] }, { "id": "PMID-10194443_T15", "type": "Protein", "text": [ "GPIIb" ], "offsets": [ [ 1027, 1032 ] ], "normalized": [] }, { "id": "PMID-10194443_T16", "type": "Protein", "text": [ "Fli-1" ], "offsets": [ [ 1074, 1079 ] ], "normalized": [] }, { "id": "PMID-10194443_T17", "type": "Protein", "text": [ "Fli-1" ], "offsets": [ [ 1150, 1155 ] ], "normalized": [] }, { "id": "PMID-10194443_T18", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 1224, 1228 ] ], "normalized": [] }, { "id": "PMID-10194443_T19", "type": "Protein", "text": [ "thrombopoietin" ], "offsets": [ [ 1311, 1325 ] ], "normalized": [] }, { "id": "PMID-10194443_T20", "type": "Protein", "text": [ "Fli-1" ], "offsets": [ [ 1354, 1359 ] ], "normalized": [] }, { "id": "PMID-10194443_T22", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 308, 316 ] ], "normalized": [] }, { "id": "PMID-10194443_T27", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 691, 699 ] ], "normalized": [] }, { "id": "PMID-10194443_T30", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1033, 1041 ] ], "normalized": [] } ]

[ { "id": "PMID-10194443_E1", "type": "Regulation", "trigger": { "text": [ "Regulation" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194443_T1" }, { "role": "Cause", "ref_id": "PMID-10194443_T2" } ] }, { "id": "PMID-10194443_E2", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 372, 379 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194443_T4" }, { "role": "Site", "ref_id": "PMID-10194443_T22" } ] }, { "id": "PMID-10194443_E3", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 432, 441 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194443_E4" } ] }, { "id": "PMID-10194443_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 456, 466 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194443_T5" } ] }, { "id": "PMID-10194443_E5", "type": "Positive_regulation", "trigger": { "text": [ "transactivate" ], "offsets": [ [ 668, 681 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194443_T9" }, { "role": "Cause", "ref_id": "PMID-10194443_T8" }, { "role": "Site", "ref_id": "PMID-10194443_T27" } ] }, { "id": "PMID-10194443_E6", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 760, 767 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194443_T11" } ] }, { "id": "PMID-10194443_E7", "type": "Positive_regulation", "trigger": { "text": [ "transactivate" ], "offsets": [ [ 970, 983 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194443_T14" }, { "role": "Cause", "ref_id": "PMID-10194443_T13" }, { "role": "Site", "ref_id": "PMID-10194443_T30" } ] }, { "id": "PMID-10194443_E8", "type": "Positive_regulation", "trigger": { "text": [ "transactivate" ], "offsets": [ [ 970, 983 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194443_T15" }, { "role": "Cause", "ref_id": "PMID-10194443_T13" }, { "role": "Site", "ref_id": "PMID-10194443_T30" } ] }, { "id": "PMID-10194443_E9", "type": "Gene_expression", "trigger": { "text": [ "identified" ], "offsets": [ [ 1063, 1073 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194443_T16" } ] }, { "id": "PMID-10194443_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1136, 1146 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10194443_T17" } ] } ]

[]

[]

[ { "id": "PMID-10197731__text", "type": "abstract", "text": [ "Studies into the effect of tyrosine phosphatase inhibitor phenylarsine oxide on NFkappaB activation in T lymphocytes during aging: evidence for altered IkappaB-alpha phosphorylation and degradation. \nNuclear Factor kappa B (NFkappaB) is a critical regulator of several genes involved in immune and inflammatory responses. Treatment of T cells with a variety of stimuli, including TNF-alpha, leads to the translocation of the active p65-50 heterodimer to the nucleus, albeit at a lower level in T cells from the elderly. We demonstrate here that pretreatment with PAO results in the inhibition of NFkappaB induction in TNF-alpha treated T cells, suggesting a role for PAO-sensitive phosphatase in the activation of the NFkappaB via this pathway in human T cells. Furthermore, it demonstrates that aging does not influence the sensitivity of this phosphatase. Treatment with DMP prior to treatment with PAO and TNF abolishes the inhibition induced by PAO, in T cells from both young and old donors, alike. Finally, we demonstrate that a failure to degrade IkappaB-alpha in cytosols of TNF-treated T cells pretreated with PAO is due to its interference with the phosphorylation of IkappaB-alpha and not due to its inhibitory effect on proteasomal degradation. These data collectively suggest that PAO interferes with the phosphorylation and the regulated degradation of IkappaB-alpha, induced by TNF, without affecting the chymotryptic activity of the proteasome, independent of age. " ], "offsets": [ [ 0, 1481 ] ] } ]

[ { "id": "PMID-10197731_T1", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 152, 165 ] ], "normalized": [] }, { "id": "PMID-10197731_T2", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 380, 389 ] ], "normalized": [] }, { "id": "PMID-10197731_T3", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 618, 627 ] ], "normalized": [] }, { "id": "PMID-10197731_T4", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1054, 1067 ] ], "normalized": [] }, { "id": "PMID-10197731_T5", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1178, 1191 ] ], "normalized": [] }, { "id": "PMID-10197731_T6", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1367, 1380 ] ], "normalized": [] } ]

[ { "id": "PMID-10197731_E1", "type": "Regulation", "trigger": { "text": [ "altered" ], "offsets": [ [ 144, 151 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10197731_E4" } ] }, { "id": "PMID-10197731_E2", "type": "Regulation", "trigger": { "text": [ "altered" ], "offsets": [ [ 144, 151 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10197731_E3" } ] }, { "id": "PMID-10197731_E3", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 166, 181 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10197731_T1" } ] }, { "id": "PMID-10197731_E4", "type": "Protein_catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 186, 197 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10197731_T1" } ] }, { "id": "PMID-10197731_E5", "type": "Protein_catabolism", "trigger": { "text": [ "degrade" ], "offsets": [ [ 1046, 1053 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10197731_T4" } ] }, { "id": "PMID-10197731_E6", "type": "Positive_regulation", "trigger": { "text": [ "due" ], "offsets": [ [ 1126, 1129 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10197731_E5" }, { "role": "Cause", "ref_id": "PMID-10197731_E7" } ] }, { "id": "PMID-10197731_E7", "type": "Negative_regulation", "trigger": { "text": [ "interference" ], "offsets": [ [ 1137, 1149 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10197731_E8" } ] }, { "id": "PMID-10197731_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1159, 1174 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10197731_T5" } ] }, { "id": "PMID-10197731_E9", "type": "Regulation", "trigger": { "text": [ "due" ], "offsets": [ [ 1200, 1203 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10197731_E5" } ] }, { "id": "PMID-10197731_E10", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1318, 1333 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10197731_T6" } ] }, { "id": "PMID-10197731_E11", "type": "Protein_catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1352, 1363 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10197731_T6" } ] } ]

[]

[]

[ { "id": "PMID-10200294__text", "type": "abstract", "text": [ "A novel lipopolysaccharide-induced transcription factor regulating tumor necrosis factor alpha gene expression: molecular cloning, sequencing, characterization, and chromosomal assignment. \nLipopolysaccharide (LPS) is a potent stimulator of monocytes and macrophages, causing secretion of tumor necrosis factor alpha (TNF-alpha) and other inflammatory mediators. Given the deleterious effects to the host of TNF-alpha, it has been postulated that TNF-alpha gene expression must be tightly regulated. The nature of the nuclear factor(s) that control TNF-alpha gene transcription in humans remains obscure, although NF-kappaB has been suggested. Our previous studies pertaining to macrophage response to LPS identified a novel DNA-binding domain located from -550 to -487 in the human TNF-alpha promoter that contains transcriptional activity, but lacks any known NF-kappaB-binding sites. We have used this DNA fragment to isolate and purify a 60-kDa protein binding to this fragment and obtained its amino-terminal sequence, which was used to design degenerate probes to screen a cDNA library from THP-1 cells. A novel cDNA clone (1.8 kb) was isolated and fully sequenced. Characterization of this cDNA clone revealed that its induction was dependent on LPS activation of THP-1 cells; hence, the name LPS-induced TNF-alpha factor (LITAF). Inhibition of LITAF mRNA expression in THP-1 cells resulted in a reduction of TNF-alpha transcripts. In addition, high level of expression of LITAF mRNA was observed predominantly in the placenta, peripheral blood leukocytes, lymph nodes, and the spleen. Finally, chromosomal localization using fluorescence in situ hybridization revealed that LITAF mapped to chromosome 16p12-16p13.3. Together, these findings suggest that LITAF plays an important role in the activation of the human TNF-alpha gene and proposes a new mechanism to control TNF-alpha gene expression. " ], "offsets": [ [ 0, 1905 ] ] } ]

[ { "id": "PMID-10200294_T1", "type": "Protein", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 67, 94 ] ], "normalized": [] }, { "id": "PMID-10200294_T2", "type": "Protein", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 289, 316 ] ], "normalized": [] }, { "id": "PMID-10200294_T3", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 318, 327 ] ], "normalized": [] }, { "id": "PMID-10200294_T4", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 408, 417 ] ], "normalized": [] }, { "id": "PMID-10200294_T5", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 447, 456 ] ], "normalized": [] }, { "id": "PMID-10200294_T6", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 549, 558 ] ], "normalized": [] }, { "id": "PMID-10200294_T7", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 783, 792 ] ], "normalized": [] }, { "id": "PMID-10200294_T8", "type": "Protein", "text": [ "LPS-induced TNF-alpha factor" ], "offsets": [ [ 1300, 1328 ] ], "normalized": [] }, { "id": "PMID-10200294_T9", "type": "Protein", "text": [ "LITAF" ], "offsets": [ [ 1330, 1335 ] ], "normalized": [] }, { "id": "PMID-10200294_T10", "type": "Protein", "text": [ "LITAF" ], "offsets": [ [ 1352, 1357 ] ], "normalized": [] }, { "id": "PMID-10200294_T11", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1416, 1425 ] ], "normalized": [] }, { "id": "PMID-10200294_T12", "type": "Protein", "text": [ "LITAF" ], "offsets": [ [ 1480, 1485 ] ], "normalized": [] }, { "id": "PMID-10200294_T13", "type": "Protein", "text": [ "LITAF" ], "offsets": [ [ 1682, 1687 ] ], "normalized": [] }, { "id": "PMID-10200294_T14", "type": "Protein", "text": [ "LITAF" ], "offsets": [ [ 1762, 1767 ] ], "normalized": [] }, { "id": "PMID-10200294_T15", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1823, 1832 ] ], "normalized": [] }, { "id": "PMID-10200294_T16", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1878, 1887 ] ], "normalized": [] }, { "id": "PMID-10200294_T25", "type": "Entity", "text": [ "DNA-binding domain" ], "offsets": [ [ 725, 743 ] ], "normalized": [] } ]

[ { "id": "PMID-10200294_E1", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 56, 66 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_E2" } ] }, { "id": "PMID-10200294_E2", "type": "Gene_expression", "trigger": { "text": [ "gene expression" ], "offsets": [ [ 95, 110 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_T1" } ] }, { "id": "PMID-10200294_E3", "type": "Positive_regulation", "trigger": { "text": [ "causing" ], "offsets": [ [ 268, 275 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_E4" } ] }, { "id": "PMID-10200294_E4", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 276, 285 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_T3" } ] }, { "id": "PMID-10200294_E5", "type": "Gene_expression", "trigger": { "text": [ "gene expression" ], "offsets": [ [ 457, 472 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_T5" } ] }, { "id": "PMID-10200294_E6", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 489, 498 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_E5" } ] }, { "id": "PMID-10200294_E7", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 541, 548 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_E8" } ] }, { "id": "PMID-10200294_E8", "type": "Transcription", "trigger": { "text": [ "gene transcription" ], "offsets": [ [ 559, 577 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_T6" } ] }, { "id": "PMID-10200294_E9", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 957, 964 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_T7" }, { "role": "Site", "ref_id": "PMID-10200294_T25" } ] }, { "id": "PMID-10200294_E10", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1226, 1235 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_T9" } ] }, { "id": "PMID-10200294_E11", "type": "Regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1240, 1249 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_E10" } ] }, { "id": "PMID-10200294_E12", "type": "Negative_regulation", "trigger": { "text": [ "Inhibition" ], "offsets": [ [ 1338, 1348 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_E13" } ] }, { "id": "PMID-10200294_E13", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 1363, 1373 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_T10" } ] }, { "id": "PMID-10200294_E14", "type": "Negative_regulation", "trigger": { "text": [ "resulted in a reduction" ], "offsets": [ [ 1389, 1412 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_E15" }, { "role": "Cause", "ref_id": "PMID-10200294_E12" } ] }, { "id": "PMID-10200294_E15", "type": "Transcription", "trigger": { "text": [ "transcripts" ], "offsets": [ [ 1426, 1437 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_T11" } ] }, { "id": "PMID-10200294_E16", "type": "Positive_regulation", "trigger": { "text": [ "high level" ], "offsets": [ [ 1452, 1462 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_E17" } ] }, { "id": "PMID-10200294_E17", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 1466, 1476 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_T12" } ] }, { "id": "PMID-10200294_E18", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 1787, 1791 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_E19" }, { "role": "Cause", "ref_id": "PMID-10200294_T14" } ] }, { "id": "PMID-10200294_E19", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1799, 1809 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_T15" } ] }, { "id": "PMID-10200294_E20", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 1870, 1877 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_E21" }, { "role": "Cause", "ref_id": "PMID-10200294_T14" } ] }, { "id": "PMID-10200294_E21", "type": "Gene_expression", "trigger": { "text": [ "gene expression" ], "offsets": [ [ 1888, 1903 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10200294_T16" } ] } ]

[ { "id": "PMID-10200294_1", "entity_ids": [ "PMID-10200294_T9", "PMID-10200294_T8" ] }, { "id": "PMID-10200294_2", "entity_ids": [ "PMID-10200294_T3", "PMID-10200294_T2" ] } ]

[]

[ { "id": "PMID-10201929__text", "type": "abstract", "text": [ "Engagement of natural cytotoxicity programs regulates AP-1 expression in the NKL human NK cell line. \nNK cell cytotoxicity is a fast and efficient mechanism of target cell lysis. Using transcription analysis, such as multiplex messenger assays, we show here that natural cytotoxicity exerted by the human NKL cell line correlates with mRNA accumulation of very early activator protein (AP)-1 transcription factor genes such as JunB, FosB and c-Fos. In addition, DNA-binding activities of Jun-Fos heterodimers were observed by electrophoretic mobility shift assays during the course of natural cytotoxicity. Interaction between immunoglobulin-like transcript-2/leukocyte Ig-like receptor 1 on NKL cells and HLA-B27 on target cells leads to an impairment of NKL natural cytotoxicity, which correlates with an absence of JunB, FosB, and c-Fos transcription, as well as an absence of their DNA-binding activity. Our studies thus indicate that, despite the rapidity of NK cell-mediated lysis, AP-1 transcription factor is activated during the early stage of NK cell cytolytic programs and that engagement of NK cell inhibitory receptors for MHC class I molecules impairs the very early activation of AP-1. " ], "offsets": [ [ 0, 1201 ] ] } ]

[ { "id": "PMID-10201929_T1", "type": "Protein", "text": [ "JunB" ], "offsets": [ [ 427, 431 ] ], "normalized": [] }, { "id": "PMID-10201929_T2", "type": "Protein", "text": [ "FosB" ], "offsets": [ [ 433, 437 ] ], "normalized": [] }, { "id": "PMID-10201929_T3", "type": "Protein", "text": [ "c-Fos" ], "offsets": [ [ 442, 447 ] ], "normalized": [] }, { "id": "PMID-10201929_T4", "type": "Protein", "text": [ "immunoglobulin-like transcript-2" ], "offsets": [ [ 627, 659 ] ], "normalized": [] }, { "id": "PMID-10201929_T5", "type": "Protein", "text": [ "leukocyte Ig-like receptor 1" ], "offsets": [ [ 660, 688 ] ], "normalized": [] }, { "id": "PMID-10201929_T6", "type": "Protein", "text": [ "HLA-B27" ], "offsets": [ [ 706, 713 ] ], "normalized": [] }, { "id": "PMID-10201929_T7", "type": "Protein", "text": [ "JunB" ], "offsets": [ [ 818, 822 ] ], "normalized": [] }, { "id": "PMID-10201929_T8", "type": "Protein", "text": [ "FosB" ], "offsets": [ [ 824, 828 ] ], "normalized": [] }, { "id": "PMID-10201929_T9", "type": "Protein", "text": [ "c-Fos" ], "offsets": [ [ 834, 839 ] ], "normalized": [] } ]

[ { "id": "PMID-10201929_E1", "type": "Positive_regulation", "trigger": { "text": [ "mRNA accumulation" ], "offsets": [ [ 335, 352 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_T3" } ] }, { "id": "PMID-10201929_E2", "type": "Positive_regulation", "trigger": { "text": [ "mRNA accumulation" ], "offsets": [ [ 335, 352 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_T1" } ] }, { "id": "PMID-10201929_E3", "type": "Positive_regulation", "trigger": { "text": [ "mRNA accumulation" ], "offsets": [ [ 335, 352 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_T2" } ] }, { "id": "PMID-10201929_E4", "type": "Binding", "trigger": { "text": [ "Interaction" ], "offsets": [ [ 607, 618 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_T4" }, { "role": "Theme", "ref_id": "PMID-10201929_T6" } ] }, { "id": "PMID-10201929_E5", "type": "Negative_regulation", "trigger": { "text": [ "absence" ], "offsets": [ [ 807, 814 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_E8" } ] }, { "id": "PMID-10201929_E6", "type": "Negative_regulation", "trigger": { "text": [ "absence" ], "offsets": [ [ 807, 814 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_E10" } ] }, { "id": "PMID-10201929_E7", "type": "Negative_regulation", "trigger": { "text": [ "absence" ], "offsets": [ [ 807, 814 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_E9" } ] }, { "id": "PMID-10201929_E8", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 840, 853 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_T7" } ] }, { "id": "PMID-10201929_E9", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 840, 853 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_T9" } ] }, { "id": "PMID-10201929_E10", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 840, 853 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_T8" } ] }, { "id": "PMID-10201929_E11", "type": "Negative_regulation", "trigger": { "text": [ "absence" ], "offsets": [ [ 869, 876 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_E15" } ] }, { "id": "PMID-10201929_E12", "type": "Negative_regulation", "trigger": { "text": [ "absence" ], "offsets": [ [ 869, 876 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_E14" } ] }, { "id": "PMID-10201929_E13", "type": "Negative_regulation", "trigger": { "text": [ "absence" ], "offsets": [ [ 869, 876 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_E16" } ] }, { "id": "PMID-10201929_E14", "type": "Binding", "trigger": { "text": [ "binding activity" ], "offsets": [ [ 890, 906 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_T8" } ] }, { "id": "PMID-10201929_E15", "type": "Binding", "trigger": { "text": [ "binding activity" ], "offsets": [ [ 890, 906 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_T7" } ] }, { "id": "PMID-10201929_E16", "type": "Binding", "trigger": { "text": [ "binding activity" ], "offsets": [ [ 890, 906 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10201929_T9" } ] } ]

[ { "id": "PMID-10201929_1", "entity_ids": [ "PMID-10201929_T4", "PMID-10201929_T5" ] } ]

[]

[ { "id": "PMID-10202024__text", "type": "abstract", "text": [ "Human cytomegalovirus binding to human monocytes induces immunoregulatory gene expression. \nTo continue our investigation of the cellular events that occur following human CMV (HCMV) infection, we focused on the regulation of cellular activation following viral binding to human monocytes. First, we showed that viral binding induced a number of immunoregulatory genes (IL-1beta, A20, NF-kappaB-p105/p50, and IkappaBalpha) in unactivated monocytes and that neutralizing Abs to the major HCMV glycoproteins, gB (UL55) and gH (UL75), inhibited the induction of these genes. Next, we demonstrated that these viral ligands directly up-regulated monocyte gene expression upon their binding to their appropriate cellular receptors. We then investigated if HCMV binding also resulted in the translation and secretion of cytokines. Our results showed that HCMV binding to monocytes resulted in the production and release of IL-1beta protein. Because these induced gene products have NF-kappaB sites in their promoter regions, we next examined whether there was an up-regulation of nuclear NF-kappaB levels. These experiments showed that, in fact, NF-kappaB was translocated to the nucleus following viral binding or purified viral ligand binding. Changes in IkappaBalpha levels correlated with the changes in NF-kappaB translocation. Lastly, we demonstrated that p38 kinase activity played a central role in IL-1beta production and that it was rapidly up-regulated following infection. These results support our hypothesis that HCMV initiates a signal transduction pathway that leads to monocyte activation and pinpoints a potential mechanism whereby HCMV infection of monocytes can result in profound pathogenesis, especially in chronic inflammatory-type conditions. " ], "offsets": [ [ 0, 1760 ] ] } ]

[ { "id": "PMID-10202024_T1", "type": "Protein", "text": [ "IL-1beta" ], "offsets": [ [ 370, 378 ] ], "normalized": [] }, { "id": "PMID-10202024_T2", "type": "Protein", "text": [ "A20" ], "offsets": [ [ 380, 383 ] ], "normalized": [] }, { "id": "PMID-10202024_T3", "type": "Protein", "text": [ "p105" ], "offsets": [ [ 395, 399 ] ], "normalized": [] }, { "id": "PMID-10202024_T4", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 400, 403 ] ], "normalized": [] }, { "id": "PMID-10202024_T5", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 409, 421 ] ], "normalized": [] }, { "id": "PMID-10202024_T6", "type": "Protein", "text": [ "IL-1beta" ], "offsets": [ [ 916, 924 ] ], "normalized": [] }, { "id": "PMID-10202024_T7", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 1250, 1262 ] ], "normalized": [] }, { "id": "PMID-10202024_T8", "type": "Protein", "text": [ "IL-1beta" ], "offsets": [ [ 1400, 1408 ] ], "normalized": [] } ]

[ { "id": "PMID-10202024_E1", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 326, 333 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_T3" } ] }, { "id": "PMID-10202024_E2", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 326, 333 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_T4" } ] }, { "id": "PMID-10202024_E3", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 326, 333 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_T5" } ] }, { "id": "PMID-10202024_E4", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 326, 333 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_T1" } ] }, { "id": "PMID-10202024_E5", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 326, 333 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_T2" } ] }, { "id": "PMID-10202024_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 532, 541 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_E15" } ] }, { "id": "PMID-10202024_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 532, 541 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_E14" } ] }, { "id": "PMID-10202024_E8", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 532, 541 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_E11" } ] }, { "id": "PMID-10202024_E9", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 532, 541 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_E13" } ] }, { "id": "PMID-10202024_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 532, 541 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_E12" } ] }, { "id": "PMID-10202024_E11", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 546, 555 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_T1" } ] }, { "id": "PMID-10202024_E12", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 546, 555 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_T5" } ] }, { "id": "PMID-10202024_E13", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 546, 555 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_T3" } ] }, { "id": "PMID-10202024_E14", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 546, 555 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_T4" } ] }, { "id": "PMID-10202024_E15", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 546, 555 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_T2" } ] }, { "id": "PMID-10202024_E16", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 874, 882 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_E18" } ] }, { "id": "PMID-10202024_E17", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 874, 882 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_E19" } ] }, { "id": "PMID-10202024_E18", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 890, 900 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_T6" } ] }, { "id": "PMID-10202024_E19", "type": "Localization", "trigger": { "text": [ "release" ], "offsets": [ [ 905, 912 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_T6" } ] }, { "id": "PMID-10202024_E20", "type": "Regulation", "trigger": { "text": [ "Changes" ], "offsets": [ [ 1239, 1246 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_T7" } ] }, { "id": "PMID-10202024_E21", "type": "Positive_regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 1392, 1396 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_E22" } ] }, { "id": "PMID-10202024_E22", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 1409, 1419 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202024_T8" } ] } ]

[]

[]

[ { "id": "PMID-10202027__text", "type": "abstract", "text": [ "Signal transduction pathways activated in endothelial cells following infection with Chlamydia pneumoniae. \nChlamydia pneumoniae is an important respiratory pathogen. Recently, its presence has been demonstrated in atherosclerotic lesions. In this study, we characterized C. pneumoniae-mediated activation of endothelial cells and demonstrated an enhanced expression of endothelial adhesion molecules followed by subsequent rolling, adhesion, and transmigration of leukocytes (monocytes, granulocytes). These effects were blocked by mAbs against endothelial and/or leukocyte adhesion molecules (beta1 and beta2 integrins). Additionally, activation of different signal transduction pathways in C. pneumoniae-infected endothelial cells was shown: protein tyrosine phosphorylation, up-regulation of phosphorylated p42/p44 mitogen-activated protein kinase, and NF-kappaB activation/translocation occurred within 10-15 min. Increased mRNA and surface expression of E-selectin, ICAM-1, and VCAM-1 were noted within hours. Thus, C. pneumoniae triggers a cascade of events that could lead to endothelial activation, inflammation, and thrombosis, which in turn may result in or may promote atherosclerosis. " ], "offsets": [ [ 0, 1198 ] ] } ]

[ { "id": "PMID-10202027_T1", "type": "Protein", "text": [ "beta1" ], "offsets": [ [ 595, 600 ] ], "normalized": [] }, { "id": "PMID-10202027_T2", "type": "Protein", "text": [ "beta2 integrins" ], "offsets": [ [ 605, 620 ] ], "normalized": [] }, { "id": "PMID-10202027_T3", "type": "Protein", "text": [ "p42" ], "offsets": [ [ 811, 814 ] ], "normalized": [] }, { "id": "PMID-10202027_T4", "type": "Protein", "text": [ "p44 mitogen-activated protein kinase" ], "offsets": [ [ 815, 851 ] ], "normalized": [] }, { "id": "PMID-10202027_T5", "type": "Protein", "text": [ "E-selectin" ], "offsets": [ [ 960, 970 ] ], "normalized": [] }, { "id": "PMID-10202027_T6", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 972, 978 ] ], "normalized": [] }, { "id": "PMID-10202027_T7", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 984, 990 ] ], "normalized": [] } ]

[ { "id": "PMID-10202027_E1", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 779, 792 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202027_T3" } ] }, { "id": "PMID-10202027_E2", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 779, 792 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202027_T4" } ] }, { "id": "PMID-10202027_E3", "type": "Positive_regulation", "trigger": { "text": [ "occurred" ], "offsets": [ [ 892, 900 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202027_E1" } ] }, { "id": "PMID-10202027_E4", "type": "Positive_regulation", "trigger": { "text": [ "Increased" ], "offsets": [ [ 919, 928 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202027_E10" } ] }, { "id": "PMID-10202027_E5", "type": "Positive_regulation", "trigger": { "text": [ "Increased" ], "offsets": [ [ 919, 928 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202027_E12" } ] }, { "id": "PMID-10202027_E6", "type": "Positive_regulation", "trigger": { "text": [ "Increased" ], "offsets": [ [ 919, 928 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202027_E14" } ] }, { "id": "PMID-10202027_E7", "type": "Positive_regulation", "trigger": { "text": [ "Increased" ], "offsets": [ [ 919, 928 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202027_E13" } ] }, { "id": "PMID-10202027_E8", "type": "Positive_regulation", "trigger": { "text": [ "Increased" ], "offsets": [ [ 919, 928 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202027_E15" } ] }, { "id": "PMID-10202027_E9", "type": "Positive_regulation", "trigger": { "text": [ "Increased" ], "offsets": [ [ 919, 928 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202027_E11" } ] }, { "id": "PMID-10202027_E10", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 946, 956 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202027_T6" } ] }, { "id": "PMID-10202027_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 946, 956 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202027_T6" } ] }, { "id": "PMID-10202027_E12", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 946, 956 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202027_T7" } ] }, { "id": "PMID-10202027_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 946, 956 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202027_T7" } ] }, { "id": "PMID-10202027_E14", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 946, 956 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202027_T5" } ] }, { "id": "PMID-10202027_E15", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 946, 956 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202027_T5" } ] } ]

[]

[]

[ { "id": "PMID-10202034__text", "type": "abstract", "text": [ "Extracellular-regulated kinase 1/2, Jun N-terminal kinase, and c-Jun are involved in NF-kappa B-dependent IL-6 expression in human monocytes. \nIn the present study we investigated the possible involvement of the mitogen-activated protein kinase family members extracellular-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) in mediating IL-6 gene expression in human monocytes, in particular their role in enhancing NF-kappa B activity. Freshly isolated monocytes treated with the protein phosphatase inhibitor okadaic acid secreted high levels of IL-6 protein, which coincided with enhanced binding activity of NF-kappa B as well as with phosphorylation and activation of the ERK1/2 and JNK proteins. The ERK pathway-specific inhibitor PD98059 inhibited IL-6 secretion from monocytes. Transient overexpression of inactive mutants of either Raf-1 or JNK1 showed that both pathways were involved in kappa B-dependent IL-6 promoter activity. By using PD98059, we demonstrated that the Raf1/MEK1/ERK1/2 pathway did not affect the DNA binding of NF-kappa B but, rather, acted at the level of transcriptional activity of NF-kappa B. Interestingly, it was shown that NF-kappa B-mediated gene transcription, both in the context of the IL-6 promoter as well as on its own, was dependent on both serine kinase activity and interaction with c-Jun protein. We conclude that okadaic acid-induced IL-6 gene expression is at least partly mediated through the ERK1/2 and JNK pathway-dependent activation of NF-kappa B transcriptional capacity. Our results suggest that the JNK pathway may regulate NF-kappa B-mediated gene transcription through its phosphorylation and activation of c-Jun. " ], "offsets": [ [ 0, 1689 ] ] } ]

[ { "id": "PMID-10202034_T1", "type": "Protein", "text": [ "Extracellular-regulated kinase 1" ], "offsets": [ [ 0, 32 ] ], "normalized": [] }, { "id": "PMID-10202034_T2", "type": "Protein", "text": [ "2" ], "offsets": [ [ 33, 34 ] ], "normalized": [] }, { "id": "PMID-10202034_T3", "type": "Protein", "text": [ "Jun N-terminal kinase" ], "offsets": [ [ 36, 57 ] ], "normalized": [] }, { "id": "PMID-10202034_T4", "type": "Protein", "text": [ "c-Jun" ], "offsets": [ [ 63, 68 ] ], "normalized": [] }, { "id": "PMID-10202034_T5", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 106, 110 ] ], "normalized": [] }, { "id": "PMID-10202034_T6", "type": "Protein", "text": [ "extracellular-regulated kinase 1" ], "offsets": [ [ 260, 292 ] ], "normalized": [] }, { "id": "PMID-10202034_T7", "type": "Protein", "text": [ "2" ], "offsets": [ [ 293, 294 ] ], "normalized": [] }, { "id": "PMID-10202034_T8", "type": "Protein", "text": [ "ERK1" ], "offsets": [ [ 296, 300 ] ], "normalized": [] }, { "id": "PMID-10202034_T9", "type": "Protein", "text": [ "2" ], "offsets": [ [ 301, 302 ] ], "normalized": [] }, { "id": "PMID-10202034_T10", "type": "Protein", "text": [ "c-Jun N-terminal kinase" ], "offsets": [ [ 308, 331 ] ], "normalized": [] }, { "id": "PMID-10202034_T11", "type": "Protein", "text": [ "JNK" ], "offsets": [ [ 333, 336 ] ], "normalized": [] }, { "id": "PMID-10202034_T12", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 351, 355 ] ], "normalized": [] }, { "id": "PMID-10202034_T13", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 562, 566 ] ], "normalized": [] }, { "id": "PMID-10202034_T14", "type": "Protein", "text": [ "JNK" ], "offsets": [ [ 702, 705 ] ], "normalized": [] }, { "id": "PMID-10202034_T15", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 769, 773 ] ], "normalized": [] }, { "id": "PMID-10202034_T16", "type": "Protein", "text": [ "Raf-1" ], "offsets": [ [ 855, 860 ] ], "normalized": [] }, { "id": "PMID-10202034_T17", "type": "Protein", "text": [ "JNK1" ], "offsets": [ [ 864, 868 ] ], "normalized": [] }, { "id": "PMID-10202034_T18", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 930, 934 ] ], "normalized": [] }, { "id": "PMID-10202034_T19", "type": "Protein", "text": [ "Raf1" ], "offsets": [ [ 997, 1001 ] ], "normalized": [] }, { "id": "PMID-10202034_T20", "type": "Protein", "text": [ "MEK1" ], "offsets": [ [ 1002, 1006 ] ], "normalized": [] }, { "id": "PMID-10202034_T21", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 1242, 1246 ] ], "normalized": [] }, { "id": "PMID-10202034_T22", "type": "Protein", "text": [ "c-Jun" ], "offsets": [ [ 1345, 1350 ] ], "normalized": [] }, { "id": "PMID-10202034_T23", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 1398, 1402 ] ], "normalized": [] }, { "id": "PMID-10202034_T24", "type": "Protein", "text": [ "JNK" ], "offsets": [ [ 1572, 1575 ] ], "normalized": [] }, { "id": "PMID-10202034_T25", "type": "Protein", "text": [ "c-Jun" ], "offsets": [ [ 1682, 1687 ] ], "normalized": [] }, { "id": "PMID-10202034_T37", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 935, 943 ] ], "normalized": [] } ]

[ { "id": "PMID-10202034_E1", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 96, 105 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_E2" } ] }, { "id": "PMID-10202034_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 111, 121 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_T5" } ] }, { "id": "PMID-10202034_E3", "type": "Positive_regulation", "trigger": { "text": [ "mediating" ], "offsets": [ [ 341, 350 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_E4" } ] }, { "id": "PMID-10202034_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 361, 371 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_T12" } ] }, { "id": "PMID-10202034_E5", "type": "Gene_expression", "trigger": { "text": [ "secreted" ], "offsets": [ [ 538, 546 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_T13" } ] }, { "id": "PMID-10202034_E6", "type": "Positive_regulation", "trigger": { "text": [ "high levels" ], "offsets": [ [ 547, 558 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_E5" } ] }, { "id": "PMID-10202034_E7", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 653, 668 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_T14" } ] }, { "id": "PMID-10202034_E8", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 673, 683 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_T14" } ] }, { "id": "PMID-10202034_E9", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 759, 768 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_E10" } ] }, { "id": "PMID-10202034_E10", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 774, 783 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_T15" } ] }, { "id": "PMID-10202034_E11", "type": "Regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 920, 929 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_T18" }, { "role": "Site", "ref_id": "PMID-10202034_T37" } ] }, { "id": "PMID-10202034_E12", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1200, 1213 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_T21" } ] }, { "id": "PMID-10202034_E13", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1283, 1292 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_E12" }, { "role": "Cause", "ref_id": "PMID-10202034_E15" } ] }, { "id": "PMID-10202034_E14", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1283, 1292 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_E12" } ] }, { "id": "PMID-10202034_E15", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1328, 1339 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_T22" } ] }, { "id": "PMID-10202034_E16", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1390, 1397 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_E17" } ] }, { "id": "PMID-10202034_E17", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1408, 1418 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_T23" } ] }, { "id": "PMID-10202034_E18", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1438, 1446 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_E16" } ] }, { "id": "PMID-10202034_E19", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1648, 1663 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_T25" } ] }, { "id": "PMID-10202034_E20", "type": "Positive_regulation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1648, 1663 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_E19" }, { "role": "Cause", "ref_id": "PMID-10202034_T24" } ] }, { "id": "PMID-10202034_E21", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1668, 1678 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202034_T25" }, { "role": "Cause", "ref_id": "PMID-10202034_T24" } ] } ]

[ { "id": "PMID-10202034_1", "entity_ids": [ "PMID-10202034_T10", "PMID-10202034_T11" ] } ]

[]

[ { "id": "PMID-10202178__text", "type": "abstract", "text": [ "Differential induction of interferon (IFN)-inducible protein 10 following differentiation of a monocyte, macrophage cell lineage is related to the changes of nuclear proteins bound to IFN stimulus response element and kappaB sites. \nWe examined chemokine gene expression following the differentiation of a monocyte, macrophage cell lineage. The human monoblastic cell line, U937 was differentiated to macrophages by the treatment with either phorbol 12-myristate 13-acetate (PMA), retinoic acid (RA), or vitamin D3 (VitD3). The gene expression of interferon (IFN)-inducible protein 10 (IP-10) (a CXC chemokine) was markedly augmented by the IFNgamma treatment in PMA- or RA-differentiated U937 cells, but only marginally in undifferentiated or VitD3-treated cells. In contrast, another inducible gene expression of monocyte chemotactic protein-1 (a CC chemokine) and the activation of the transcriptional factor (FcRFgamma) bound to the gamma response region were similarly or less abundantly induced by IFNgamma treatment in PMA- or RA-differentiated U937 cells, indicating that increased IP-10 mRNA induction was not due to the augmented ability of the cells to respond to the presence of IFNgamma. Increased expression of IFNgamma-induced IP-10 mRNA following the differentiation of U937 cells was mediated largely by augmented transcriptional activity of the gene and was related to differentiation-dependent changes of the proteins bound to IFN stimulus response element (ISRE) and kB sites, suggesting that these nuclear proteins may determine the IP-10 mRNA inducibility by IFNgamma. " ], "offsets": [ [ 0, 1591 ] ] } ]

[ { "id": "PMID-10202178_T1", "type": "Protein", "text": [ "interferon (IFN)-inducible protein 10" ], "offsets": [ [ 26, 63 ] ], "normalized": [] }, { "id": "PMID-10202178_T2", "type": "Protein", "text": [ "interferon (IFN)-inducible protein 10" ], "offsets": [ [ 547, 584 ] ], "normalized": [] }, { "id": "PMID-10202178_T3", "type": "Protein", "text": [ "IP-10" ], "offsets": [ [ 586, 591 ] ], "normalized": [] }, { "id": "PMID-10202178_T4", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 641, 649 ] ], "normalized": [] }, { "id": "PMID-10202178_T5", "type": "Protein", "text": [ "monocyte chemotactic protein-1" ], "offsets": [ [ 815, 845 ] ], "normalized": [] }, { "id": "PMID-10202178_T6", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1004, 1012 ] ], "normalized": [] }, { "id": "PMID-10202178_T7", "type": "Protein", "text": [ "IP-10" ], "offsets": [ [ 1090, 1095 ] ], "normalized": [] }, { "id": "PMID-10202178_T8", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1191, 1199 ] ], "normalized": [] }, { "id": "PMID-10202178_T9", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1225, 1233 ] ], "normalized": [] }, { "id": "PMID-10202178_T10", "type": "Protein", "text": [ "IP-10" ], "offsets": [ [ 1242, 1247 ] ], "normalized": [] }, { "id": "PMID-10202178_T11", "type": "Protein", "text": [ "IP-10" ], "offsets": [ [ 1554, 1559 ] ], "normalized": [] }, { "id": "PMID-10202178_T12", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1581, 1589 ] ], "normalized": [] } ]

[ { "id": "PMID-10202178_E1", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 13, 22 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_T1" } ] }, { "id": "PMID-10202178_E2", "type": "Positive_regulation", "trigger": { "text": [ "following" ], "offsets": [ [ 64, 73 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_E1" } ] }, { "id": "PMID-10202178_E3", "type": "Gene_expression", "trigger": { "text": [ "gene expression" ], "offsets": [ [ 528, 543 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_T3" } ] }, { "id": "PMID-10202178_E4", "type": "Positive_regulation", "trigger": { "text": [ "augmented" ], "offsets": [ [ 624, 633 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_E3" }, { "role": "Cause", "ref_id": "PMID-10202178_T4" } ] }, { "id": "PMID-10202178_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 801, 811 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_T5" } ] }, { "id": "PMID-10202178_E6", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 993, 1000 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_E5" }, { "role": "Cause", "ref_id": "PMID-10202178_T6" } ] }, { "id": "PMID-10202178_E7", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1080, 1089 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_E8" } ] }, { "id": "PMID-10202178_E8", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1101, 1110 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_T7" } ] }, { "id": "PMID-10202178_E9", "type": "Positive_regulation", "trigger": { "text": [ "due" ], "offsets": [ [ 1119, 1122 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_E7" } ] }, { "id": "PMID-10202178_E10", "type": "Positive_regulation", "trigger": { "text": [ "Increased" ], "offsets": [ [ 1201, 1210 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_E12" } ] }, { "id": "PMID-10202178_E11", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 1211, 1221 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_T10" } ] }, { "id": "PMID-10202178_E12", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1234, 1241 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_E11" }, { "role": "Cause", "ref_id": "PMID-10202178_T9" } ] }, { "id": "PMID-10202178_E13", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1301, 1309 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_E10" }, { "role": "Cause", "ref_id": "PMID-10202178_E14" } ] }, { "id": "PMID-10202178_E14", "type": "Positive_regulation", "trigger": { "text": [ "augmented" ], "offsets": [ [ 1321, 1330 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_E15" } ] }, { "id": "PMID-10202178_E15", "type": "Positive_regulation", "trigger": { "text": [ "transcriptional activity" ], "offsets": [ [ 1331, 1355 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_T10" } ] }, { "id": "PMID-10202178_E16", "type": "Regulation", "trigger": { "text": [ "determine" ], "offsets": [ [ 1540, 1549 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_E17" } ] }, { "id": "PMID-10202178_E17", "type": "Positive_regulation", "trigger": { "text": [ "inducibility" ], "offsets": [ [ 1565, 1577 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202178_T12" }, { "role": "Cause", "ref_id": "PMID-10202178_T11" } ] } ]

[ { "id": "PMID-10202178_1", "entity_ids": [ "PMID-10202178_T3", "PMID-10202178_T2" ] } ]

[]

[ { "id": "PMID-10202937__text", "type": "abstract", "text": [ "Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling. \nFludarabine is a nucleoside analog used in the treatment of hematologic malignancies that can induce severe and prolonged immunosuppression. Although it can be incorporated into the DNA of dividing cells, fludarabine is also a potent inhibitor of cells with a low growth fraction, thus it must have other mechanisms of action. STAT1, which is activated in response to many lymphocyte-activating cytokines including the interferons, is essential for cell-mediated immunity, as the absence of this protein is associated with prominent defects in the ability to control viral infections. Here we show that fludarabine, but not the immunosuppressant cyclosporine A, inhibits the cytokine-induced activation of STAT1 and STAT1-dependent gene transcription in normal resting or activated lymphocytes. Fludarabine caused a specific depletion of STAT1 protein (and mRNA) but not of other STATs. This loss of STAT1 was also seen in cells from patients treated with fludarabine in vivo. Brief exposure to fludarabine led to a sustained loss of STAT1, analogous to the prolonged period of immunosuppression induced by exposure to the drug in vivo. Thus, STAT1 may be a useful target in the development of new immunosuppressive and antineoplastic agents. " ], "offsets": [ [ 0, 1332 ] ] } ]

[ { "id": "PMID-10202937_T1", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 71, 76 ] ], "normalized": [] }, { "id": "PMID-10202937_T2", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 416, 421 ] ], "normalized": [] }, { "id": "PMID-10202937_T3", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 795, 800 ] ], "normalized": [] }, { "id": "PMID-10202937_T4", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 805, 810 ] ], "normalized": [] }, { "id": "PMID-10202937_T5", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 927, 932 ] ], "normalized": [] }, { "id": "PMID-10202937_T6", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 989, 994 ] ], "normalized": [] }, { "id": "PMID-10202937_T7", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 1123, 1128 ] ], "normalized": [] }, { "id": "PMID-10202937_T8", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 1232, 1237 ] ], "normalized": [] } ]

[ { "id": "PMID-10202937_E1", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 432, 441 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202937_T2" } ] }, { "id": "PMID-10202937_E2", "type": "Negative_regulation", "trigger": { "text": [ "absence" ], "offsets": [ [ 569, 576 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202937_T2" } ] }, { "id": "PMID-10202937_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 751, 759 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202937_E4" } ] }, { "id": "PMID-10202937_E4", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 781, 791 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202937_T3" } ] }, { "id": "PMID-10202937_E5", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 896, 902 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202937_E6" } ] }, { "id": "PMID-10202937_E6", "type": "Negative_regulation", "trigger": { "text": [ "depletion" ], "offsets": [ [ 914, 923 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202937_T5" } ] }, { "id": "PMID-10202937_E7", "type": "Negative_regulation", "trigger": { "text": [ "loss" ], "offsets": [ [ 981, 985 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202937_T6" } ] }, { "id": "PMID-10202937_E8", "type": "Positive_regulation", "trigger": { "text": [ "led" ], "offsets": [ [ 1096, 1099 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202937_E9" } ] }, { "id": "PMID-10202937_E9", "type": "Negative_regulation", "trigger": { "text": [ "loss" ], "offsets": [ [ 1115, 1119 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10202937_T7" } ] } ]

[]

[]

[ { "id": "PMID-10203577__text", "type": "abstract", "text": [ "Suppressive effects of anti-inflammatory agents on human endothelial cell activation and induction of heat shock proteins. \nBACKGROUND: Studies from our laboratory have shown that the earliest stages of atherosclerosis may be mediated by an autoimmune reaction against heat shock protein 60 (Hsp60). The interactions of Hsp60-specific T cells with arterial endothelial cells (EC) require expression of both Hsp60 and certain adhesion molecules shown to be induced simultaneously in EC by mechanical and other types of stress. Recently, it was shown that suppression of T cell-mediated immune responses by cyclosporin A (CyA) enhanced atherosclerotic lesion formation in mice. In contrast, aspirin was found to lower the risk of myocardial infarction in men. These conflicting observations may be due to different effects of anti-inflammatory agents on adhesion molecule and Hsp expression in EC, respectively. MATERIAL AND METHODS: In the present study, we analyzed the effects of CyA, aspirin, and indomethacin on T cell proliferation using a proliferation assay. To explore the expression of adhesion molecules, monocyte chemoattractant protein-1 (MCP-1), and Hsp60 in human umbilical vein endothelial cells (HUVECs), Northern blot analyses were used. To examine the activation status of the transcription factors nuclear factor kappaB (NF-kappaB) and heat shock factor-1 (HSF-1), electrophoretic mobility shift assays were performed. RESULTS: With the exception of indomethacin, the used immunosuppressive and anti-inflammatory agents significantly inhibited T cell proliferation in response to influenza virus antigen in a dose-dependent manner. Interestingly, CyA and indomethacin did not suppress tumor necrosis factor-alpha (TNF-alpha)-induced adhesion molecule expression on HUVECs, whereas aspirin had an inhibitory effect. These observations correlated with the modulation of NF-kappaB activity in EC. All agents tested induced expression of Hsp60 6 hr after application. In addition, aspirin and indomethacin, but not CyA, induced Hsp70 expression in HUVECs that correlated with induction of HSF-1 activity. CONCLUSION: Our results show that the tested agents (except indomethacin) are inhibitors of the T cell-mediated immune response, as expected, that aspirin is an effective suppressor of adhesion molecule expression, and that all three agents can induce Hsp60 in HUVECs. These data provide the molecular basis for the notion that (1) part of the anti-atherogenic effect of aspirin may be due to the prevention of the adhesion of sensitized T cells to stressed EC; (2) that part of the atherosclerosis-promoting effect of CyA may be due to its potential as an inducer of Hsp60 expression and its inability to down-regulate adhesion molecule expression on EC; and (3) that down-regulation of MCP-1 expression by aspirin may result in decreased recruitment of monocytes into the arterial intima beneath stressed EC. " ], "offsets": [ [ 0, 2930 ] ] } ]

[ { "id": "PMID-10203577_T1", "type": "Protein", "text": [ "heat shock protein 60" ], "offsets": [ [ 269, 290 ] ], "normalized": [] }, { "id": "PMID-10203577_T2", "type": "Protein", "text": [ "Hsp60" ], "offsets": [ [ 292, 297 ] ], "normalized": [] }, { "id": "PMID-10203577_T3", "type": "Protein", "text": [ "Hsp60" ], "offsets": [ [ 320, 325 ] ], "normalized": [] }, { "id": "PMID-10203577_T4", "type": "Protein", "text": [ "Hsp60" ], "offsets": [ [ 407, 412 ] ], "normalized": [] }, { "id": "PMID-10203577_T5", "type": "Protein", "text": [ "monocyte chemoattractant protein-1" ], "offsets": [ [ 1114, 1148 ] ], "normalized": [] }, { "id": "PMID-10203577_T6", "type": "Protein", "text": [ "MCP-1" ], "offsets": [ [ 1150, 1155 ] ], "normalized": [] }, { "id": "PMID-10203577_T7", "type": "Protein", "text": [ "Hsp60" ], "offsets": [ [ 1162, 1167 ] ], "normalized": [] }, { "id": "PMID-10203577_T8", "type": "Protein", "text": [ "heat shock factor-1" ], "offsets": [ [ 1354, 1373 ] ], "normalized": [] }, { "id": "PMID-10203577_T9", "type": "Protein", "text": [ "HSF-1" ], "offsets": [ [ 1375, 1380 ] ], "normalized": [] }, { "id": "PMID-10203577_T10", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 1703, 1730 ] ], "normalized": [] }, { "id": "PMID-10203577_T11", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1732, 1741 ] ], "normalized": [] }, { "id": "PMID-10203577_T12", "type": "Protein", "text": [ "Hsp60" ], "offsets": [ [ 1952, 1957 ] ], "normalized": [] }, { "id": "PMID-10203577_T13", "type": "Protein", "text": [ "Hsp70" ], "offsets": [ [ 2042, 2047 ] ], "normalized": [] }, { "id": "PMID-10203577_T14", "type": "Protein", "text": [ "HSF-1" ], "offsets": [ [ 2103, 2108 ] ], "normalized": [] }, { "id": "PMID-10203577_T15", "type": "Protein", "text": [ "Hsp60" ], "offsets": [ [ 2371, 2376 ] ], "normalized": [] }, { "id": "PMID-10203577_T16", "type": "Protein", "text": [ "Hsp60" ], "offsets": [ [ 2687, 2692 ] ], "normalized": [] }, { "id": "PMID-10203577_T17", "type": "Protein", "text": [ "MCP-1" ], "offsets": [ [ 2807, 2812 ] ], "normalized": [] } ]

[ { "id": "PMID-10203577_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 388, 398 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10203577_T4" } ] }, { "id": "PMID-10203577_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1080, 1090 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10203577_T7" } ] }, { "id": "PMID-10203577_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1080, 1090 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10203577_T6" } ] }, { "id": "PMID-10203577_E4", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1269, 1279 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10203577_T9" } ] }, { "id": "PMID-10203577_E5", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1930, 1937 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10203577_E6" } ] }, { "id": "PMID-10203577_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1938, 1948 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10203577_T12" } ] }, { "id": "PMID-10203577_E7", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 2034, 2041 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10203577_E8" } ] }, { "id": "PMID-10203577_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2048, 2058 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10203577_T13" } ] }, { "id": "PMID-10203577_E9", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 2090, 2099 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10203577_T14" } ] }, { "id": "PMID-10203577_E10", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 2364, 2370 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10203577_T15" } ] }, { "id": "PMID-10203577_E11", "type": "Positive_regulation", "trigger": { "text": [ "inducer" ], "offsets": [ [ 2676, 2683 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10203577_E12" } ] }, { "id": "PMID-10203577_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2693, 2703 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10203577_T16" } ] }, { "id": "PMID-10203577_E13", "type": "Negative_regulation", "trigger": { "text": [ "down-regulation" ], "offsets": [ [ 2788, 2803 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10203577_E14" } ] }, { "id": "PMID-10203577_E14", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2813, 2823 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10203577_T17" } ] } ]

[ { "id": "PMID-10203577_1", "entity_ids": [ "PMID-10203577_T1", "PMID-10203577_T2" ] }, { "id": "PMID-10203577_2", "entity_ids": [ "PMID-10203577_T9", "PMID-10203577_T8" ] }, { "id": "PMID-10203577_3", "entity_ids": [ "PMID-10203577_T6", "PMID-10203577_T5" ] }, { "id": "PMID-10203577_4", "entity_ids": [ "PMID-10203577_T10", "PMID-10203577_T11" ] } ]

[]

[ { "id": "PMID-10206480__text", "type": "abstract", "text": [ "Amelioration of rat cerulein pancreatitis by guamerin-derived peptide, a novel elastase inhibitor. \nIncreased activity of various proteases is observed in both human and experimental pancreatitis; however, the information on the effects of specific protease inhibitors on the disease is limited. In this study we show that a novel elastase inhibitor, guamerin-derived synthetic peptide (GDSP), improves the parameters of cerulein-induced acute pancreatitis in the rat. The effects of GDSP on pancreatic weight, serum amylase and lipase, morphologic changes in the pancreas, neutrophil infiltration, and nuclear factor KB (NF-KB) activation were measured in rats infused with supramaximal dose of cerulein (5 (g/kg/h) for 6 h. The effects of GDSP were also measured on superoxide formation by activated human neutrophils. The effects of GDSP were compared with those of another elastase inhibitor, elastatinal. GDSP significantly inhibited edema formation, neutrophil infiltration, acinar cell damage, and plasma lipase and amylase increases caused by cerulein. GDSP also completely inhibited superoxide formation in the human neutrophils stimulated by N-formyl-methionine-leucine-phenyl-alanine (fMLP) or 12-O-tetradecanoylphorbol-13-acetate (TPA). Elastatinal had some of the same effects as GDSP but was less potent and effective. These results demonstrate a beneficial effect of GDSP, a novel specific elastase inhibitor, on the development of rat cerulein pancreatitis. " ], "offsets": [ [ 0, 1474 ] ] } ]

[]

[]

[]

[]

[ { "id": "PMID-10206983__text", "type": "abstract", "text": [ "Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP). \nActivation of T lymphocytes to produce cytokines is regulated by the counterbalance of protein-tyrosine kinases and protein-tyrosine phosphatases, many of which have a high degree of substrate specificity because of physical association with their targets. Overexpression of hematopoietic protein-tyrosine phosphatase (HePTP) results in suppression of T lymphocyte activation as measured by T cell antigen receptor-induced activation of transcription factors binding to the 5' promoter of the interleukin-2 gene. Efforts to pinpoint the exact site of action and specificity of HePTP in the signaling cascade revealed that HePTP acts directly on the mitogen-activated protein (MAP) kinases Erk1 and 2 and consequently reduces the magnitude and duration of their catalytic activation in intact T cells. In contrast, HePTP had no effects on N-terminal c-Jun kinase or on events upstream of the MAP kinases. The specificity of HePTP correlated with its physical association through its noncatalytic N terminus with Erk and another MAP kinase, p38, but not Jnk or other proteins. We propose that HePTP plays a negative role in antigen receptor signaling by specifically regulating MAP kinases in the cytosol and at early time points of T cell activation before the activation-induced expression of nuclear dual-specific MAP kinase phosphatases. " ], "offsets": [ [ 0, 1461 ] ] } ]

[ { "id": "PMID-10206983_T1", "type": "Protein", "text": [ "hematopoietic tyrosine phosphatase" ], "offsets": [ [ 76, 110 ] ], "normalized": [] }, { "id": "PMID-10206983_T2", "type": "Protein", "text": [ "HePTP" ], "offsets": [ [ 112, 117 ] ], "normalized": [] }, { "id": "PMID-10206983_T3", "type": "Protein", "text": [ "hematopoietic protein-tyrosine phosphatase" ], "offsets": [ [ 396, 438 ] ], "normalized": [] }, { "id": "PMID-10206983_T4", "type": "Protein", "text": [ "HePTP" ], "offsets": [ [ 440, 445 ] ], "normalized": [] }, { "id": "PMID-10206983_T5", "type": "Protein", "text": [ "interleukin-2" ], "offsets": [ [ 614, 627 ] ], "normalized": [] }, { "id": "PMID-10206983_T6", "type": "Protein", "text": [ "HePTP" ], "offsets": [ [ 698, 703 ] ], "normalized": [] }, { "id": "PMID-10206983_T7", "type": "Protein", "text": [ "HePTP" ], "offsets": [ [ 743, 748 ] ], "normalized": [] }, { "id": "PMID-10206983_T8", "type": "Protein", "text": [ "Erk1" ], "offsets": [ [ 810, 814 ] ], "normalized": [] }, { "id": "PMID-10206983_T9", "type": "Protein", "text": [ "2" ], "offsets": [ [ 819, 820 ] ], "normalized": [] }, { "id": "PMID-10206983_T10", "type": "Protein", "text": [ "HePTP" ], "offsets": [ [ 935, 940 ] ], "normalized": [] }, { "id": "PMID-10206983_T11", "type": "Protein", "text": [ "HePTP" ], "offsets": [ [ 1044, 1049 ] ], "normalized": [] }, { "id": "PMID-10206983_T12", "type": "Protein", "text": [ "HePTP" ], "offsets": [ [ 1212, 1217 ] ], "normalized": [] } ]

[ { "id": "PMID-10206983_E1", "type": "Gene_expression", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 378, 392 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10206983_T4" } ] }, { "id": "PMID-10206983_E2", "type": "Positive_regulation", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 378, 392 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10206983_T4" } ] }, { "id": "PMID-10206983_E3", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 544, 554 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10206983_E4" } ] }, { "id": "PMID-10206983_E4", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 580, 587 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10206983_T5" } ] }, { "id": "PMID-10206983_E5", "type": "Regulation", "trigger": { "text": [ "acts" ], "offsets": [ [ 749, 753 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10206983_T9" }, { "role": "Cause", "ref_id": "PMID-10206983_T7" } ] }, { "id": "PMID-10206983_E6", "type": "Regulation", "trigger": { "text": [ "acts" ], "offsets": [ [ 749, 753 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10206983_T8" }, { "role": "Cause", "ref_id": "PMID-10206983_T7" } ] }, { "id": "PMID-10206983_E7", "type": "Negative_regulation", "trigger": { "text": [ "reduces" ], "offsets": [ [ 838, 845 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10206983_E9" }, { "role": "Cause", "ref_id": "PMID-10206983_T7" } ] }, { "id": "PMID-10206983_E8", "type": "Negative_regulation", "trigger": { "text": [ "reduces" ], "offsets": [ [ 838, 845 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10206983_E10" }, { "role": "Cause", "ref_id": "PMID-10206983_T7" } ] }, { "id": "PMID-10206983_E9", "type": "Positive_regulation", "trigger": { "text": [ "catalytic activation" ], "offsets": [ [ 882, 902 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10206983_T9" } ] }, { "id": "PMID-10206983_E10", "type": "Positive_regulation", "trigger": { "text": [ "catalytic activation" ], "offsets": [ [ 882, 902 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10206983_T8" } ] }, { "id": "PMID-10206983_E11", "type": "Binding", "trigger": { "text": [ "physical association" ], "offsets": [ [ 1070, 1090 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10206983_T11" } ] } ]

[ { "id": "PMID-10206983_1", "entity_ids": [ "PMID-10206983_T1", "PMID-10206983_T2" ] }, { "id": "PMID-10206983_2", "entity_ids": [ "PMID-10206983_T4", "PMID-10206983_T3" ] } ]

[]

[ { "id": "PMID-10208867__text", "type": "abstract", "text": [ "Angiotensin II activates the proinflammatory transcription factor nuclear factor-kappaB in human monocytes. \nThe renin-angiotensin system may contribute to the pathogenesis of atherosclerosis. A common feature of all stages of atherosclerosis is inflammation of the vessel wall. The transcription factor nuclear factor-kappaB (NF-kappaB) participates in most signaling pathways involved in inflammation. This study therefore examined the effect of angiotensin (ANG) II on NF-kappaB activation in monocytic cells, a major cellular component of human atheroma, by electrophoretic mobility shift assay. ANG II, like TNFalpha, caused rapid activation of NF-kappaB in human mononuclear cells isolated from peripheral blood by Ficoll density gradient. This ANG II effect was blocked by the angiotensin AT1 receptor antagonist losartan. Specificity of ANG II-induced NF-kappaB activation was ascertained by supershift and competition experiments. Moreover, ANG II stimulated NF-kappaB activation in human monocytes, but not in lymphocytes from the same preparation. Together, the data demonstrate the ability of the vasoactive peptide ANG II to activate inflammatory pathways in human monocytes. Copyright 1999 Academic Press. " ], "offsets": [ [ 0, 1220 ] ] } ]

[ { "id": "PMID-10208867_T1", "type": "Protein", "text": [ "TNFalpha" ], "offsets": [ [ 613, 621 ] ], "normalized": [] }, { "id": "PMID-10208867_T2", "type": "Protein", "text": [ "angiotensin AT1 receptor" ], "offsets": [ [ 784, 808 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-10209036__text", "type": "abstract", "text": [ "SHP2-interacting transmembrane adaptor protein (SIT), a novel disulfide-linked dimer regulating human T cell activation. \nT lymphocytes express several low molecular weight transmembrane adaptor proteins that recruit src homology (SH)2 domain-containing intracellular molecules to the cell membrane via tyrosine-based signaling motifs. We describe here a novel molecule of this group termed SIT (SHP2 interacting transmembrane adaptor protein). SIT is a disulfide-linked homodimeric glycoprotein that is expressed in lymphocytes. After tyrosine phosphorylation by src and possibly syk protein tyrosine kinases SIT recruits the SH2 domain-containing tyrosine phosphatase SHP2 via an immunoreceptor tyrosine-based inhibition motif. Overexpression of SIT in Jurkat cells downmodulates T cell receptor- and phytohemagglutinin-mediated activation of the nuclear factor of activated T cells (NF-AT) by interfering with signaling processes that are probably located upstream of activation of phospholipase C. However, binding of SHP2 to SIT is not required for inhibition of NF-AT induction, suggesting that SIT not only regulates NF-AT activity but also controls NF-AT unrelated pathways of T cell activation involving SHP2. " ], "offsets": [ [ 0, 1219 ] ] } ]

[ { "id": "PMID-10209036_T1", "type": "Protein", "text": [ "SHP2-interacting transmembrane adaptor protein" ], "offsets": [ [ 0, 46 ] ], "normalized": [] }, { "id": "PMID-10209036_T2", "type": "Protein", "text": [ "SIT" ], "offsets": [ [ 48, 51 ] ], "normalized": [] }, { "id": "PMID-10209036_T3", "type": "Protein", "text": [ "SIT" ], "offsets": [ [ 391, 394 ] ], "normalized": [] }, { "id": "PMID-10209036_T4", "type": "Protein", "text": [ "SHP2 interacting transmembrane adaptor protein" ], "offsets": [ [ 396, 442 ] ], "normalized": [] }, { "id": "PMID-10209036_T5", "type": "Protein", "text": [ "SIT" ], "offsets": [ [ 445, 448 ] ], "normalized": [] }, { "id": "PMID-10209036_T6", "type": "Protein", "text": [ "src" ], "offsets": [ [ 564, 567 ] ], "normalized": [] }, { "id": "PMID-10209036_T7", "type": "Protein", "text": [ "syk" ], "offsets": [ [ 581, 584 ] ], "normalized": [] }, { "id": "PMID-10209036_T8", "type": "Protein", "text": [ "SIT" ], "offsets": [ [ 610, 613 ] ], "normalized": [] }, { "id": "PMID-10209036_T9", "type": "Protein", "text": [ "SHP2" ], "offsets": [ [ 670, 674 ] ], "normalized": [] }, { "id": "PMID-10209036_T10", "type": "Protein", "text": [ "SIT" ], "offsets": [ [ 748, 751 ] ], "normalized": [] }, { "id": "PMID-10209036_T11", "type": "Protein", "text": [ "phytohemagglutinin" ], "offsets": [ [ 803, 821 ] ], "normalized": [] }, { "id": "PMID-10209036_T12", "type": "Protein", "text": [ "SHP2" ], "offsets": [ [ 1022, 1026 ] ], "normalized": [] }, { "id": "PMID-10209036_T13", "type": "Protein", "text": [ "SIT" ], "offsets": [ [ 1030, 1033 ] ], "normalized": [] }, { "id": "PMID-10209036_T14", "type": "Protein", "text": [ "SIT" ], "offsets": [ [ 1101, 1104 ] ], "normalized": [] }, { "id": "PMID-10209036_T15", "type": "Protein", "text": [ "SHP2" ], "offsets": [ [ 1213, 1217 ] ], "normalized": [] }, { "id": "PMID-10209036_T17", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 536, 544 ] ], "normalized": [] } ]

[ { "id": "PMID-10209036_E1", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 504, 513 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209036_T5" } ] }, { "id": "PMID-10209036_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 545, 560 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209036_T8" }, { "role": "Site", "ref_id": "PMID-10209036_T17" } ] }, { "id": "PMID-10209036_E3", "type": "Positive_regulation", "trigger": { "text": [ "by" ], "offsets": [ [ 561, 563 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209036_E2" }, { "role": "Cause", "ref_id": "PMID-10209036_T6" } ] }, { "id": "PMID-10209036_E4", "type": "Positive_regulation", "trigger": { "text": [ "by" ], "offsets": [ [ 561, 563 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209036_E2" }, { "role": "Cause", "ref_id": "PMID-10209036_T7" } ] }, { "id": "PMID-10209036_E5", "type": "Gene_expression", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 730, 744 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209036_T10" } ] }, { "id": "PMID-10209036_E6", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1011, 1018 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209036_T12" }, { "role": "Theme", "ref_id": "PMID-10209036_T13" } ] } ]

[ { "id": "PMID-10209036_1", "entity_ids": [ "PMID-10209036_T1", "PMID-10209036_T2" ] }, { "id": "PMID-10209036_2", "entity_ids": [ "PMID-10209036_T3", "PMID-10209036_T4" ] } ]

[]

[ { "id": "PMID-10209041__text", "type": "abstract", "text": [ "GrpL, a Grb2-related adaptor protein, interacts with SLP-76 to regulate nuclear factor of activated T cell activation. \nPropagation of signals from the T cell antigen receptor (TCR) involves a number of adaptor molecules. SH2 domain-containing protein 76 (SLP-76) interacts with the guanine nucleotide exchange factor Vav to activate the nuclear factor of activated cells (NF-AT), and its expression is required for normal T cell development. We report the cloning and characterization of a novel Grb2-like adaptor molecule designated as Grb2-related protein of the lymphoid system (GrpL). Expression of GrpL is restricted to hematopoietic tissues, and it is distinguished from Grb2 by having a proline-rich region. GrpL can be coimmunoprecipitated with SLP-76 but not with Sos1 or Sos2 from Jurkat cell lysates. In contrast, Grb2 can be coimmunoprecipitated with Sos1 and Sos2 but not with SLP-76. Moreover, tyrosine-phosphorylated LAT/pp36/38 in detergent lysates prepared from anti-CD3 stimulated T cells associated with Grb2 but not GrpL. These data reveal the presence of distinct complexes involving GrpL and Grb2 in T cells. A functional role of the GrpL-SLP-76 complex is suggested by the ability of GrpL to act alone or in concert with SLP-76 to augment NF-AT activation in Jurkat T cells. " ], "offsets": [ [ 0, 1299 ] ] } ]

[ { "id": "PMID-10209041_T1", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-10209041_T2", "type": "Protein", "text": [ "Grb2" ], "offsets": [ [ 8, 12 ] ], "normalized": [] }, { "id": "PMID-10209041_T3", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 53, 59 ] ], "normalized": [] }, { "id": "PMID-10209041_T4", "type": "Protein", "text": [ "SH2 domain-containing protein 76" ], "offsets": [ [ 222, 254 ] ], "normalized": [] }, { "id": "PMID-10209041_T5", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 256, 262 ] ], "normalized": [] }, { "id": "PMID-10209041_T6", "type": "Protein", "text": [ "Vav" ], "offsets": [ [ 318, 321 ] ], "normalized": [] }, { "id": "PMID-10209041_T7", "type": "Protein", "text": [ "Grb2" ], "offsets": [ [ 497, 501 ] ], "normalized": [] }, { "id": "PMID-10209041_T8", "type": "Protein", "text": [ "Grb2-related protein of the lymphoid system" ], "offsets": [ [ 538, 581 ] ], "normalized": [] }, { "id": "PMID-10209041_T9", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 583, 587 ] ], "normalized": [] }, { "id": "PMID-10209041_T10", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 604, 608 ] ], "normalized": [] }, { "id": "PMID-10209041_T11", "type": "Protein", "text": [ "Grb2" ], "offsets": [ [ 678, 682 ] ], "normalized": [] }, { "id": "PMID-10209041_T12", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 716, 720 ] ], "normalized": [] }, { "id": "PMID-10209041_T13", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 754, 760 ] ], "normalized": [] }, { "id": "PMID-10209041_T14", "type": "Protein", "text": [ "Sos1" ], "offsets": [ [ 774, 778 ] ], "normalized": [] }, { "id": "PMID-10209041_T15", "type": "Protein", "text": [ "Sos2" ], "offsets": [ [ 782, 786 ] ], "normalized": [] }, { "id": "PMID-10209041_T16", "type": "Protein", "text": [ "Grb2" ], "offsets": [ [ 826, 830 ] ], "normalized": [] }, { "id": "PMID-10209041_T17", "type": "Protein", "text": [ "Sos1" ], "offsets": [ [ 864, 868 ] ], "normalized": [] }, { "id": "PMID-10209041_T18", "type": "Protein", "text": [ "Sos2" ], "offsets": [ [ 873, 877 ] ], "normalized": [] }, { "id": "PMID-10209041_T19", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 891, 897 ] ], "normalized": [] }, { "id": "PMID-10209041_T20", "type": "Protein", "text": [ "LAT" ], "offsets": [ [ 933, 936 ] ], "normalized": [] }, { "id": "PMID-10209041_T21", "type": "Protein", "text": [ "pp36/38" ], "offsets": [ [ 937, 944 ] ], "normalized": [] }, { "id": "PMID-10209041_T22", "type": "Protein", "text": [ "Grb2" ], "offsets": [ [ 1024, 1028 ] ], "normalized": [] }, { "id": "PMID-10209041_T23", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 1037, 1041 ] ], "normalized": [] }, { "id": "PMID-10209041_T24", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 1106, 1110 ] ], "normalized": [] }, { "id": "PMID-10209041_T25", "type": "Protein", "text": [ "Grb2" ], "offsets": [ [ 1115, 1119 ] ], "normalized": [] }, { "id": "PMID-10209041_T26", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 1157, 1161 ] ], "normalized": [] }, { "id": "PMID-10209041_T27", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 1162, 1168 ] ], "normalized": [] }, { "id": "PMID-10209041_T28", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 1208, 1212 ] ], "normalized": [] }, { "id": "PMID-10209041_T29", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 1245, 1251 ] ], "normalized": [] }, { "id": "PMID-10209041_T36", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 909, 917 ] ], "normalized": [] } ]

[ { "id": "PMID-10209041_E1", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 38, 47 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209041_T1" }, { "role": "Theme", "ref_id": "PMID-10209041_T3" } ] }, { "id": "PMID-10209041_E2", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 264, 273 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209041_T5" }, { "role": "Theme", "ref_id": "PMID-10209041_T6" } ] }, { "id": "PMID-10209041_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 389, 399 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209041_T5" } ] }, { "id": "PMID-10209041_E4", "type": "Gene_expression", "trigger": { "text": [ "Expression" ], "offsets": [ [ 590, 600 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209041_T10" } ] }, { "id": "PMID-10209041_E5", "type": "Binding", "trigger": { "text": [ "coimmunoprecipitated" ], "offsets": [ [ 728, 748 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209041_T12" }, { "role": "Theme", "ref_id": "PMID-10209041_T14" } ] }, { "id": "PMID-10209041_E6", "type": "Binding", "trigger": { "text": [ "coimmunoprecipitated" ], "offsets": [ [ 728, 748 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209041_T12" }, { "role": "Theme", "ref_id": "PMID-10209041_T15" } ] }, { "id": "PMID-10209041_E7", "type": "Binding", "trigger": { "text": [ "coimmunoprecipitated" ], "offsets": [ [ 728, 748 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209041_T12" }, { "role": "Theme", "ref_id": "PMID-10209041_T13" } ] }, { "id": "PMID-10209041_E8", "type": "Binding", "trigger": { "text": [ "coimmunoprecipitated" ], "offsets": [ [ 838, 858 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209041_T16" }, { "role": "Theme", "ref_id": "PMID-10209041_T17" } ] }, { "id": "PMID-10209041_E9", "type": "Binding", "trigger": { "text": [ "coimmunoprecipitated" ], "offsets": [ [ 838, 858 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209041_T16" }, { "role": "Theme", "ref_id": "PMID-10209041_T19" } ] }, { "id": "PMID-10209041_E10", "type": "Binding", "trigger": { "text": [ "coimmunoprecipitated" ], "offsets": [ [ 838, 858 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209041_T16" }, { "role": "Theme", "ref_id": "PMID-10209041_T18" } ] }, { "id": "PMID-10209041_E11", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 918, 932 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209041_T20" }, { "role": "Site", "ref_id": "PMID-10209041_T36" } ] }, { "id": "PMID-10209041_E12", "type": "Binding", "trigger": { "text": [ "associated" ], "offsets": [ [ 1008, 1018 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209041_T20" }, { "role": "Theme", "ref_id": "PMID-10209041_T22" } ] }, { "id": "PMID-10209041_E13", "type": "Binding", "trigger": { "text": [ "associated" ], "offsets": [ [ 1008, 1018 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10209041_T20" }, { "role": "Theme", "ref_id": "PMID-10209041_T23" } ] } ]

[ { "id": "PMID-10209041_1", "entity_ids": [ "PMID-10209041_T8", "PMID-10209041_T9" ] }, { "id": "PMID-10209041_2", "entity_ids": [ "PMID-10209041_T20", "PMID-10209041_T21" ] }, { "id": "PMID-10209041_3", "entity_ids": [ "PMID-10209041_T5", "PMID-10209041_T4" ] } ]

[]

[ { "id": "PMID-10210321__text", "type": "abstract", "text": [ "Unexpected and coordinated expression of Spi-1, Fli-1, and megakaryocytic genes in four Epo-dependent cell lines established from transgenic mice displaying erythroid-specific expression of a thermosensitive SV40 T antigen. \nMost erythroleukemic cell lines established in vitro coexpress erythrocytic and megakaryocytic markers that often are associated with expression of Spi-1 and/or Fli-1 transcription factors known as transactivators of megakaryocyte-specific promoters. In the present study, we examined the possibility of establishing new cell lines keeping strictly erythroid-specific properties in vitro through the targeted and conditional immortalization of erythrocytic progenitors. For that purpose, we established several lines of transgenic mice displaying erythroid-specific expression of a thermosensitive SV40 T antigen. As expected, these transgenic mice developed splenomegaly due to the massive amplification of Ter 119 positive erythroid nucleated cells expressing T antigen. Despite this drastic effect in vivo, the in vitro immortalization of erythropoietin-dependent erythroid progenitors unexpectedly occurred at low frequency, and all four cell lines established expressed both erythrocytic (globins) and megakaryocytic markers (glycoprotein IIb, platelet factor 4) as well as Spi-1 and Fli-1 transcripts at permissive temperature. Switching the cells to the nonpermissive temperature led to a marked increase in globin gene expression and concomitant decrease in expression of Spi-1, Fli-1, and megakaryocytic genes in an erythropoietin-dependent manner. Interestingly, enhanced expression of Spi-1 and Fli-1 genes already was detected in the Ter 119 positive cell population of transgenic mice spleen in vivo. However, like normal Ter 119 erythroid cells, these Ter 119 positive cells from transgenic mice still expressed high levels of beta-globin and very low or undetectable glycoprotein IIb and platelet factor 4 megakaryocytic transcripts. Taken together, these data indicate that the unexpected expression of megakaryocytic genes is a specific property of immortalized cells that cannot be explained only by enhanced expression of Spi-1 and/or Fli-1 genes. " ], "offsets": [ [ 0, 2192 ] ] } ]

[ { "id": "PMID-10210321_T1", "type": "Protein", "text": [ "Spi-1" ], "offsets": [ [ 41, 46 ] ], "normalized": [] }, { "id": "PMID-10210321_T2", "type": "Protein", "text": [ "Fli-1" ], "offsets": [ [ 48, 53 ] ], "normalized": [] }, { "id": "PMID-10210321_T3", "type": "Protein", "text": [ "Epo" ], "offsets": [ [ 88, 91 ] ], "normalized": [] }, { "id": "PMID-10210321_T4", "type": "Protein", "text": [ "Spi-1" ], "offsets": [ [ 373, 378 ] ], "normalized": [] }, { "id": "PMID-10210321_T5", "type": "Protein", "text": [ "Fli-1" ], "offsets": [ [ 386, 391 ] ], "normalized": [] }, { "id": "PMID-10210321_T6", "type": "Protein", "text": [ "erythropoietin" ], "offsets": [ [ 1067, 1081 ] ], "normalized": [] }, { "id": "PMID-10210321_T7", "type": "Protein", "text": [ "glycoprotein IIb" ], "offsets": [ [ 1256, 1272 ] ], "normalized": [] }, { "id": "PMID-10210321_T8", "type": "Protein", "text": [ "platelet factor 4" ], "offsets": [ [ 1274, 1291 ] ], "normalized": [] }, { "id": "PMID-10210321_T9", "type": "Protein", "text": [ "Spi-1" ], "offsets": [ [ 1304, 1309 ] ], "normalized": [] }, { "id": "PMID-10210321_T10", "type": "Protein", "text": [ "Fli-1" ], "offsets": [ [ 1314, 1319 ] ], "normalized": [] }, { "id": "PMID-10210321_T11", "type": "Protein", "text": [ "Spi-1" ], "offsets": [ [ 1505, 1510 ] ], "normalized": [] }, { "id": "PMID-10210321_T12", "type": "Protein", "text": [ "Fli-1" ], "offsets": [ [ 1512, 1517 ] ], "normalized": [] }, { "id": "PMID-10210321_T13", "type": "Protein", "text": [ "erythropoietin" ], "offsets": [ [ 1550, 1564 ] ], "normalized": [] }, { "id": "PMID-10210321_T14", "type": "Protein", "text": [ "Spi-1" ], "offsets": [ [ 1621, 1626 ] ], "normalized": [] }, { "id": "PMID-10210321_T15", "type": "Protein", "text": [ "Fli-1" ], "offsets": [ [ 1631, 1636 ] ], "normalized": [] }, { "id": "PMID-10210321_T16", "type": "Protein", "text": [ "beta-globin" ], "offsets": [ [ 1866, 1877 ] ], "normalized": [] }, { "id": "PMID-10210321_T17", "type": "Protein", "text": [ "glycoprotein IIb" ], "offsets": [ [ 1907, 1923 ] ], "normalized": [] }, { "id": "PMID-10210321_T18", "type": "Protein", "text": [ "platelet factor 4" ], "offsets": [ [ 1928, 1945 ] ], "normalized": [] }, { "id": "PMID-10210321_T19", "type": "Protein", "text": [ "Spi-1" ], "offsets": [ [ 2166, 2171 ] ], "normalized": [] }, { "id": "PMID-10210321_T20", "type": "Protein", "text": [ "Fli-1" ], "offsets": [ [ 2179, 2184 ] ], "normalized": [] } ]

[ { "id": "PMID-10210321_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 27, 37 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T2" } ] }, { "id": "PMID-10210321_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 27, 37 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T1" } ] }, { "id": "PMID-10210321_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 359, 369 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T4" } ] }, { "id": "PMID-10210321_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 359, 369 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T5" } ] }, { "id": "PMID-10210321_E5", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1190, 1199 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T7" } ] }, { "id": "PMID-10210321_E6", "type": "Transcription", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1190, 1199 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T9" } ] }, { "id": "PMID-10210321_E7", "type": "Transcription", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1190, 1199 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T10" } ] }, { "id": "PMID-10210321_E8", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1190, 1199 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T8" } ] }, { "id": "PMID-10210321_E9", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 1479, 1487 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_E12" } ] }, { "id": "PMID-10210321_E10", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 1479, 1487 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_E11" } ] }, { "id": "PMID-10210321_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1491, 1501 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T11" } ] }, { "id": "PMID-10210321_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1491, 1501 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T12" } ] }, { "id": "PMID-10210321_E13", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1565, 1574 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_E9" }, { "role": "Cause", "ref_id": "PMID-10210321_T13" } ] }, { "id": "PMID-10210321_E14", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1565, 1574 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_E10" }, { "role": "Cause", "ref_id": "PMID-10210321_T13" } ] }, { "id": "PMID-10210321_E15", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1607, 1617 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T15" } ] }, { "id": "PMID-10210321_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1607, 1617 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T14" } ] }, { "id": "PMID-10210321_E17", "type": "Transcription", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1841, 1850 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T18" } ] }, { "id": "PMID-10210321_E18", "type": "Transcription", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1841, 1850 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T17" } ] }, { "id": "PMID-10210321_E19", "type": "Transcription", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1841, 1850 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T16" } ] }, { "id": "PMID-10210321_E20", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 2143, 2151 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_E22" } ] }, { "id": "PMID-10210321_E21", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 2143, 2151 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_E23" } ] }, { "id": "PMID-10210321_E22", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2152, 2162 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T19" } ] }, { "id": "PMID-10210321_E23", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2152, 2162 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210321_T20" } ] } ]

[]

[]

[ { "id": "PMID-10210645__text", "type": "abstract", "text": [ "LPS-Induced NF-kappaB activation and TNF-alpha release in human monocytes are protein tyrosine kinase dependent and protein kinase C independent. \nBACKGROUND: Tumor necrosis factor alpha (TNF-alpha) is an important mediator of septic shock. Endotoxin (LPS) signal transduction in human monocytes leads to activation of nuclear factor-kappa B (NF-kappaB) and TNF-alpha release. Previous studies have implicated activation of both protein kinase C (PKC) and protein tyrosine kinases (PTK) in LPS-induced NF-kappaB activation and TNF-alpha production. We hypothesized that inhibition of either PKC or PTK would decrease LPS-induced NF-kappaB DNA binding and TNF-alpha release in human monocytes. MATERIALS AND METHODS: Human monocytes were stimulated with PMA (50 ng/ml) alone or LPS (100 ng/ml) with and without a nonspecific serine/threonine protein kinase inhibitor staurosporine (Stauro), a specific pan-PKC inhibitor bisindolylmaleimide (Bis), or an inhibitor of PTK genistein (Gen). TNF-alpha release in culture supernatants was measured by an ELISA. NF-kappaB DNA binding was evaluated by electrophoretic mobility shift assay. RESULTS: LPS increased NF-kappaB DNA binding and TNF-alpha release in human monocytes. Nonspecific protein kinase inhibition inhibited NF-kappaB activation and TNF-alpha release, while specific PKC inhibition with Bis had no effect on LPS-induced NF-kappaB DNA binding or TNF-alpha release. PTK inhibition with Gen attenuated both LPS-induced NF-kappaB DNA binding and TNF-alpha production in human monocytes. Direct activation of PKC with PMA induced both NF-kappaB activation and TNF-alpha production by human monocytes. CONCLUSIONS: These results suggest that LPS-induced NF-kappaB activation and TNF-alpha release in human monocytes are independent of PKC activity. Furthermore, our results provide evidence that PTK plays a role in LPS-induced NF-kappaB activation and TNF-alpha release in human monocytes and thus could be a potential therapeutic target in inflammatory states. Copyright 1999 Academic Press. " ], "offsets": [ [ 0, 2046 ] ] } ]

[ { "id": "PMID-10210645_T1", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 37, 46 ] ], "normalized": [] }, { "id": "PMID-10210645_T2", "type": "Protein", "text": [ "Tumor necrosis factor alpha" ], "offsets": [ [ 159, 186 ] ], "normalized": [] }, { "id": "PMID-10210645_T3", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 188, 197 ] ], "normalized": [] }, { "id": "PMID-10210645_T4", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 358, 367 ] ], "normalized": [] }, { "id": "PMID-10210645_T5", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 527, 536 ] ], "normalized": [] }, { "id": "PMID-10210645_T6", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 655, 664 ] ], "normalized": [] }, { "id": "PMID-10210645_T7", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 986, 995 ] ], "normalized": [] }, { "id": "PMID-10210645_T8", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1180, 1189 ] ], "normalized": [] }, { "id": "PMID-10210645_T9", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1291, 1300 ] ], "normalized": [] }, { "id": "PMID-10210645_T10", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1403, 1412 ] ], "normalized": [] }, { "id": "PMID-10210645_T11", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1500, 1509 ] ], "normalized": [] }, { "id": "PMID-10210645_T12", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1613, 1622 ] ], "normalized": [] }, { "id": "PMID-10210645_T13", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1731, 1740 ] ], "normalized": [] }, { "id": "PMID-10210645_T14", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1905, 1914 ] ], "normalized": [] } ]

[ { "id": "PMID-10210645_E1", "type": "Positive_regulation", "trigger": { "text": [ "Induced" ], "offsets": [ [ 4, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_E2" } ] }, { "id": "PMID-10210645_E2", "type": "Localization", "trigger": { "text": [ "release" ], "offsets": [ [ 47, 54 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_T1" } ] }, { "id": "PMID-10210645_E3", "type": "Positive_regulation", "trigger": { "text": [ "leads" ], "offsets": [ [ 296, 301 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_E4" } ] }, { "id": "PMID-10210645_E4", "type": "Localization", "trigger": { "text": [ "release" ], "offsets": [ [ 368, 375 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_T4" } ] }, { "id": "PMID-10210645_E5", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 494, 501 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_E6" } ] }, { "id": "PMID-10210645_E6", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 537, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_T5" } ] }, { "id": "PMID-10210645_E7", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1144, 1153 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_E8" } ] }, { "id": "PMID-10210645_E8", "type": "Localization", "trigger": { "text": [ "release" ], "offsets": [ [ 1190, 1197 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_T8" } ] }, { "id": "PMID-10210645_E9", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1256, 1265 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_E10" } ] }, { "id": "PMID-10210645_E10", "type": "Localization", "trigger": { "text": [ "release" ], "offsets": [ [ 1301, 1308 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_T9" } ] }, { "id": "PMID-10210645_E11", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1356, 1362 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_E12" } ] }, { "id": "PMID-10210645_E12", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1370, 1377 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_E13" } ] }, { "id": "PMID-10210645_E13", "type": "Localization", "trigger": { "text": [ "release" ], "offsets": [ [ 1413, 1420 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_T10" } ] }, { "id": "PMID-10210645_E14", "type": "Negative_regulation", "trigger": { "text": [ "attenuated" ], "offsets": [ [ 1446, 1456 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_E15" } ] }, { "id": "PMID-10210645_E15", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1466, 1473 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_E16" } ] }, { "id": "PMID-10210645_E16", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 1510, 1520 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_T11" } ] }, { "id": "PMID-10210645_E17", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1575, 1582 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_E18" } ] }, { "id": "PMID-10210645_E18", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 1623, 1633 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_T12" } ] }, { "id": "PMID-10210645_E19", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1698, 1705 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_E20" } ] }, { "id": "PMID-10210645_E20", "type": "Localization", "trigger": { "text": [ "release" ], "offsets": [ [ 1741, 1748 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_T13" } ] }, { "id": "PMID-10210645_E21", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1872, 1879 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_E22" } ] }, { "id": "PMID-10210645_E22", "type": "Localization", "trigger": { "text": [ "release" ], "offsets": [ [ 1915, 1922 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10210645_T14" } ] } ]

[ { "id": "PMID-10210645_1", "entity_ids": [ "PMID-10210645_T2", "PMID-10210645_T3" ] } ]

[]

[ { "id": "PMID-10217534__text", "type": "abstract", "text": [ "Cellular disposition of sulphamethoxazole and its metabolites: implications for hypersensitivity. \n1. Bioactivation of sulphamethoxazole (SMX) to chemically-reactive metabolites and subsequent protein conjugation is thought to be involved in SMX hypersensitivity. We have therefore examined the cellular metabolism, disposition and conjugation of SMX and its metabolites in vitro. 2. Flow cytometry revealed binding of N-hydroxy (SMX-NHOH) and nitroso (SMX-NO) metabolites of SMX, but not of SMX itself, to the surface of viable white blood cells. Cellular haptenation by SMX-NO was reduced by exogenous glutathione (GSH). 3. SMX-NHOH and SMX-NO were rapidly reduced back to the parent compound by cysteine (CYS), GSH, human peripheral blood cells and plasma, suggesting that this is an important and ubiquitous bioinactivation mechanism. 4. Fluorescence HPLC showed that SMX-NHOH and SMX-NO depleted CYS and GSH in buffer, and to a lesser extent, in cells and plasma. 5. Neutrophil apoptosis and inhibition of neutrophil function were induced at lower concentrations of SMX-NHOH and SMX-NO than those inducing loss of membrane viability, with SMX having no effect. Lymphocytes were significantly (P<0.05) more sensitive to the direct cytotoxic effects of SMX-NO than neutrophils. 6. Partitioning of SMX-NHOH into red blood cells was significantly (P<0.05) lower than with the hydroxylamine of dapsone. 7. Our results suggest that the balance between oxidation of SMX to its toxic metabolites and their reduction is an important protective cellular mechanism. If an imbalance exists, haptenation of the toxic metabolites to bodily proteins including the surface of viable cells can occur, and may result in drug hypersensitivity. " ], "offsets": [ [ 0, 1730 ] ] } ]

[]

[]

[]

[]

[ { "id": "PMID-10221643__text", "type": "abstract", "text": [ "Tcf-1-mediated transcription in T lymphocytes: differential role for glycogen synthase kinase-3 in fibroblasts and T cells. \nBeta-catenin is the vertebrate homolog of the Drosophila segment polarity gene Armadillo and plays roles in both cell-cell adhesion and transduction of the Wnt signaling cascade. Recently, members of the Lef/Tcf transcription factor family have been identified as protein partners of beta-catenin, explaining how beta-catenin alters gene expression. Here we report that in T cells, Tcf-1 also becomes transcriptionally active through interaction with beta-catenin, suggesting that the Wnt signal transduction pathway is operational in T lymphocytes as well. However, although Wnt signals are known to inhibit the activity of the negative regulatory protein kinase glycogen synthase kinase-3beta (GSK-3beta), resulting in increased levels of beta-catenin, we find no evidence for involvement of GSK-3beta in Tcf-mediated transcription in T cells. That is, a dominant negative GSK-3beta does not specifically activate Tcf transcription and stimuli (lithium or phytohemagglutinin) that inhibit GSK-3beta activity also do not activate Tcf reporter genes. Thus, inhibition of GSK-3beta is insufficient to activate Tcf-dependent transcription in T lymphocytes. In contrast, in C57MG fibroblast cells, lithium inactivates GSK-3beta and induces Tcf-controlled transcription. This is the first demonstration that lithium can alter gene expression of Tcf-responsive genes, and points to a difference in regulation of Wnt signaling between fibroblasts and lymphocytes. " ], "offsets": [ [ 0, 1583 ] ] } ]

[ { "id": "PMID-10221643_T1", "type": "Protein", "text": [ "Tcf-1" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-10221643_T2", "type": "Protein", "text": [ "glycogen synthase kinase-3" ], "offsets": [ [ 69, 95 ] ], "normalized": [] }, { "id": "PMID-10221643_T3", "type": "Protein", "text": [ "Beta-catenin" ], "offsets": [ [ 125, 137 ] ], "normalized": [] }, { "id": "PMID-10221643_T4", "type": "Protein", "text": [ "beta-catenin" ], "offsets": [ [ 409, 421 ] ], "normalized": [] }, { "id": "PMID-10221643_T5", "type": "Protein", "text": [ "beta-catenin" ], "offsets": [ [ 438, 450 ] ], "normalized": [] }, { "id": "PMID-10221643_T6", "type": "Protein", "text": [ "Tcf-1" ], "offsets": [ [ 507, 512 ] ], "normalized": [] }, { "id": "PMID-10221643_T7", "type": "Protein", "text": [ "beta-catenin" ], "offsets": [ [ 576, 588 ] ], "normalized": [] }, { "id": "PMID-10221643_T8", "type": "Protein", "text": [ "glycogen synthase kinase-3beta" ], "offsets": [ [ 789, 819 ] ], "normalized": [] }, { "id": "PMID-10221643_T9", "type": "Protein", "text": [ "GSK-3beta" ], "offsets": [ [ 821, 830 ] ], "normalized": [] }, { "id": "PMID-10221643_T10", "type": "Protein", "text": [ "beta-catenin" ], "offsets": [ [ 866, 878 ] ], "normalized": [] }, { "id": "PMID-10221643_T11", "type": "Protein", "text": [ "GSK-3beta" ], "offsets": [ [ 919, 928 ] ], "normalized": [] }, { "id": "PMID-10221643_T12", "type": "Protein", "text": [ "GSK-3beta" ], "offsets": [ [ 1000, 1009 ] ], "normalized": [] }, { "id": "PMID-10221643_T13", "type": "Protein", "text": [ "phytohemagglutinin" ], "offsets": [ [ 1083, 1101 ] ], "normalized": [] }, { "id": "PMID-10221643_T14", "type": "Protein", "text": [ "GSK-3beta" ], "offsets": [ [ 1116, 1125 ] ], "normalized": [] }, { "id": "PMID-10221643_T15", "type": "Protein", "text": [ "GSK-3beta" ], "offsets": [ [ 1196, 1205 ] ], "normalized": [] }, { "id": "PMID-10221643_T16", "type": "Protein", "text": [ "GSK-3beta" ], "offsets": [ [ 1340, 1349 ] ], "normalized": [] }, { "id": "PMID-10221643_T17", "type": "Protein", "text": [ "Tcf" ], "offsets": [ [ 1362, 1365 ] ], "normalized": [] } ]

[ { "id": "PMID-10221643_E1", "type": "Positive_regulation", "trigger": { "text": [ "becomes transcriptionally active" ], "offsets": [ [ 518, 550 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10221643_T6" }, { "role": "Cause", "ref_id": "PMID-10221643_E2" } ] }, { "id": "PMID-10221643_E2", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 559, 570 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10221643_T6" }, { "role": "Theme", "ref_id": "PMID-10221643_T7" } ] }, { "id": "PMID-10221643_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 726, 733 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10221643_T9" } ] }, { "id": "PMID-10221643_E4", "type": "Positive_regulation", "trigger": { "text": [ "increased levels" ], "offsets": [ [ 846, 862 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10221643_T10" }, { "role": "Cause", "ref_id": "PMID-10221643_E3" } ] }, { "id": "PMID-10221643_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1108, 1115 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10221643_T14" }, { "role": "Cause", "ref_id": "PMID-10221643_T13" } ] }, { "id": "PMID-10221643_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1108, 1115 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10221643_T14" } ] }, { "id": "PMID-10221643_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1182, 1192 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10221643_T15" } ] }, { "id": "PMID-10221643_E8", "type": "Negative_regulation", "trigger": { "text": [ "inactivates" ], "offsets": [ [ 1328, 1339 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10221643_T16" } ] } ]

[ { "id": "PMID-10221643_1", "entity_ids": [ "PMID-10221643_T9", "PMID-10221643_T8" ] } ]

[]

[ { "id": "PMID-10221658__text", "type": "abstract", "text": [ "CIITA-induced occupation of MHC class II promoters is independent of the cooperative stabilization of the promoter-bound multi-protein complexes. \nPrecise regulation of MHC class II expression plays a crucial role in the control of the immune response. The transactivator CIITA behaves as a master controller of constitutive and inducible MHC class II gene activation, but its exact mechanism of action is not known. Activation of MHC class II promoters requires binding of at least three distinct multi-protein complexes (RFX, X2BP and NF-Y). It is known that the stability of this binding results from cooperative interactions between these proteins. We show here that expression of CIITA in MHC class II- cells triggers occupation of the promoters by these complexes. This observation raised the possibility that the effect of CIITA on promoter occupation is mediated by an effect on the cooperative stabilization of the DNA-bound multi-protein complexes. We show, however, that the presence of CIITA does not affect the stability of the higher-order protein complex formed on DNA by RFX, X2BP and NF-Y. This suggests other mechanisms for CIITA-induced promoter occupancy, such as an effect on chromatin structure leading to increased accessibility of MHC class II promoters. This ability of CIITA to facilitate promoter occupation is undissociable from its transactivation potential. Finally, we conclude that this effect of CIITA is cell-type specific, since expression of CIITA is not required for normal occupation of MHC class II promoters in B lymphocytes. " ], "offsets": [ [ 0, 1566 ] ] } ]

[ { "id": "PMID-10221658_T1", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-10221658_T2", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 272, 277 ] ], "normalized": [] }, { "id": "PMID-10221658_T3", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 685, 690 ] ], "normalized": [] }, { "id": "PMID-10221658_T4", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 830, 835 ] ], "normalized": [] }, { "id": "PMID-10221658_T5", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 998, 1003 ] ], "normalized": [] }, { "id": "PMID-10221658_T6", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 1142, 1147 ] ], "normalized": [] }, { "id": "PMID-10221658_T7", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 1295, 1300 ] ], "normalized": [] }, { "id": "PMID-10221658_T8", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 1429, 1434 ] ], "normalized": [] }, { "id": "PMID-10221658_T9", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 1478, 1483 ] ], "normalized": [] } ]

[ { "id": "PMID-10221658_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 671, 681 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10221658_T3" } ] }, { "id": "PMID-10221658_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1464, 1474 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10221658_T9" } ] } ]

[]

[]

[ { "id": "PMID-10224109__text", "type": "abstract", "text": [ "Immunosuppressant PG490 (triptolide) inhibits T-cell interleukin-2 expression at the level of purine-box/nuclear factor of activated T-cells and NF-kappaB transcriptional activation. \nPG490 (triptolide) is a diterpene triepoxide with potent immunosuppressive and antiinflammatory properties. PG490 inhibits interleukin(IL)-2 expression by normal human peripheral blood lymphocytes stimulated with phorbol 12-myristate 13-acetate (PMA) and antibody to CD3 (IC50 of 10 ng/ml), and with PMA and ionomycin (Iono, IC50 of 40 ng/ml). In Jurkat T-cells, PG490 inhibits PMA/Iono-stimulated IL-2 transcription. PG490 inhibits the induction of DNA binding activity at the purine-box/antigen receptor response element (ARRE)/nuclear factor of activated T-cells (NF-AT) target sequence but not at the NF-kappaB site. PG490 can completely inhibit transcriptional activation at the purine-box/ARRE/NF-AT and NF-kappaB target DNA sequences triggered by all stimuli examined (PMA, PMA/Iono, tumor necrosis factor-alpha). PG490 also inhibits PMA-stimulated activation of a chimeric transcription factor in which the C-terminal TA1 transactivation domain of NF-kappaB p65 is fused to the DNA binding domain of GAL4. In 16HBE human bronchial epithelial cells, IL-8 expression is regulated predominantly by NF-kappaB, and PG490 but not cyclosporin A can completely inhibit expression of IL-8. The mechanism of PG490 inhibition of cytokine gene expression differs from cyclosporin A and involves nuclear inhibition of transcriptional activation of NF-kappaB and the purine-box regulator operating at the ARRE/NF-AT site at a step after specific DNA binding. " ], "offsets": [ [ 0, 1637 ] ] } ]

[ { "id": "PMID-10224109_T1", "type": "Protein", "text": [ "interleukin-2" ], "offsets": [ [ 53, 66 ] ], "normalized": [] }, { "id": "PMID-10224109_T2", "type": "Protein", "text": [ "interleukin(IL)-2" ], "offsets": [ [ 307, 324 ] ], "normalized": [] }, { "id": "PMID-10224109_T3", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 582, 586 ] ], "normalized": [] }, { "id": "PMID-10224109_T4", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 975, 1002 ] ], "normalized": [] }, { "id": "PMID-10224109_T5", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1150, 1153 ] ], "normalized": [] }, { "id": "PMID-10224109_T6", "type": "Protein", "text": [ "GAL4" ], "offsets": [ [ 1192, 1196 ] ], "normalized": [] }, { "id": "PMID-10224109_T7", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 1241, 1245 ] ], "normalized": [] }, { "id": "PMID-10224109_T8", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 1367, 1371 ] ], "normalized": [] } ]

[ { "id": "PMID-10224109_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 37, 45 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224109_E2" } ] }, { "id": "PMID-10224109_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 67, 77 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224109_T1" } ] }, { "id": "PMID-10224109_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 298, 306 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224109_E4" } ] }, { "id": "PMID-10224109_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 325, 335 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224109_T2" } ] }, { "id": "PMID-10224109_E5", "type": "Negative_regulation", "trigger": { "text": [ "PG490" ], "offsets": [ [ 547, 552 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224109_E6" } ] }, { "id": "PMID-10224109_E6", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 571, 581 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224109_E7" } ] }, { "id": "PMID-10224109_E7", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 587, 600 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224109_T3" } ] }, { "id": "PMID-10224109_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1246, 1256 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224109_T7" } ] }, { "id": "PMID-10224109_E9", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1260, 1269 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224109_E8" } ] }, { "id": "PMID-10224109_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1345, 1352 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224109_E11" } ] }, { "id": "PMID-10224109_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1353, 1363 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224109_T8" } ] } ]

[]

[]

[ { "id": "PMID-10225377__text", "type": "abstract", "text": [ "Activation of nuclear factor-kappaB by lipopolysaccharide in mononuclear leukocytes is prevented by inhibitors of cytosolic phospholipase A2. \nIn monocytes, lipopolysaccharide induces synthesis and activity of the 85-kDa cytosolic phospholipase A2. This enzyme releases arachidonic acid and lyso-phospholipids from membranes which are metabolized to eicosanoids and platelet-activating-factor. These lipid mediators increase activity of transcription factors and expression of cytokine genes indicating a function for cytosolic phospholipase A2 in signal transduction and inflammation. We have shown previously that trifluoromethylketone inhibitors of cytosolic phospholipase A2 suppressed interleukin-1beta protein and steady-state mRNA levels in human lipopolysaccharide-stimulated peripheral blood mononuclear leukocytes. In this study, the subcellular mechanisms were analyzed by which trifluoromethylketones interfere with gene expression. We found that they reduced the initial interleukin-1beta mRNA transcription rate through prevention of degradation of inhibitor-kappaB alpha. Consequently, cytosolic activation, nuclear translocation and DNA-binding of nuclear factor-kappaB were decreased. Trifluoromethylketones ameliorate chronic inflammation in vivo. Thus, this therapeutic potency may reside in retention of inactive nuclear factor-kappaB in the cytosol thereby abrogating interleukin-1beta gene transcription. " ], "offsets": [ [ 0, 1427 ] ] } ]

[ { "id": "PMID-10225377_T1", "type": "Protein", "text": [ "interleukin-1beta" ], "offsets": [ [ 690, 707 ] ], "normalized": [] }, { "id": "PMID-10225377_T2", "type": "Protein", "text": [ "interleukin-1beta" ], "offsets": [ [ 984, 1001 ] ], "normalized": [] }, { "id": "PMID-10225377_T3", "type": "Protein", "text": [ "inhibitor-kappaB alpha" ], "offsets": [ [ 1063, 1085 ] ], "normalized": [] }, { "id": "PMID-10225377_T4", "type": "Protein", "text": [ "interleukin-1beta" ], "offsets": [ [ 1389, 1406 ] ], "normalized": [] } ]

[ { "id": "PMID-10225377_E1", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 679, 689 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10225377_T1" } ] }, { "id": "PMID-10225377_E2", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 964, 971 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10225377_E3" } ] }, { "id": "PMID-10225377_E3", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1007, 1020 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10225377_T2" } ] }, { "id": "PMID-10225377_E4", "type": "Protein_catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1048, 1059 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10225377_T3" } ] }, { "id": "PMID-10225377_E5", "type": "Negative_regulation", "trigger": { "text": [ "abrogating" ], "offsets": [ [ 1378, 1388 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10225377_E6" } ] }, { "id": "PMID-10225377_E6", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1412, 1425 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10225377_T4" } ] } ]

[]

[]

[ { "id": "PMID-10226884__text", "type": "abstract", "text": [ "Molecular regulation of cytokine gene expression during the immune response. \nCytokine expression by immune system cells plays an important role in the regulation of the immune response. On first encounter with antigen, naive CD4+ T helper (Th) cells differentiate into cytokine-producing effector cells. Two types of effector cells characterized by their distinct expression of cytokine profiles have been described. Th1 cells produce IL-2 and IFN-gamma, whereas Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13. In many pathological situations, the balance between Th1 and Th2 immune responses determines the outcome of diverse immunologically mediated clinical syndromes including infectious, autoimmune, and allergic diseases. However, the molecular basis for the tissue-specific expression of Th1/Th2-like cytokines has remained elusive. In this review we evaluate the possible in vivo role of different transcription factors and transcriptional mechanisms in T cell differentiation and the immune response. " ], "offsets": [ [ 0, 1017 ] ] } ]

[ { "id": "PMID-10226884_T1", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 226, 229 ] ], "normalized": [] }, { "id": "PMID-10226884_T2", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 436, 440 ] ], "normalized": [] }, { "id": "PMID-10226884_T3", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 445, 454 ] ], "normalized": [] }, { "id": "PMID-10226884_T4", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 482, 486 ] ], "normalized": [] }, { "id": "PMID-10226884_T5", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 488, 492 ] ], "normalized": [] }, { "id": "PMID-10226884_T6", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 494, 498 ] ], "normalized": [] }, { "id": "PMID-10226884_T7", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 500, 505 ] ], "normalized": [] }, { "id": "PMID-10226884_T8", "type": "Protein", "text": [ "IL-13" ], "offsets": [ [ 511, 516 ] ], "normalized": [] } ]

[ { "id": "PMID-10226884_E1", "type": "Gene_expression", "trigger": { "text": [ "produce" ], "offsets": [ [ 428, 435 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10226884_T2" } ] }, { "id": "PMID-10226884_E2", "type": "Gene_expression", "trigger": { "text": [ "produce" ], "offsets": [ [ 428, 435 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10226884_T3" } ] }, { "id": "PMID-10226884_E3", "type": "Gene_expression", "trigger": { "text": [ "produce" ], "offsets": [ [ 474, 481 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10226884_T6" } ] }, { "id": "PMID-10226884_E4", "type": "Gene_expression", "trigger": { "text": [ "produce" ], "offsets": [ [ 474, 481 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10226884_T4" } ] }, { "id": "PMID-10226884_E5", "type": "Gene_expression", "trigger": { "text": [ "produce" ], "offsets": [ [ 474, 481 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10226884_T5" } ] }, { "id": "PMID-10226884_E6", "type": "Gene_expression", "trigger": { "text": [ "produce" ], "offsets": [ [ 474, 481 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10226884_T8" } ] }, { "id": "PMID-10226884_E7", "type": "Gene_expression", "trigger": { "text": [ "produce" ], "offsets": [ [ 474, 481 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10226884_T7" } ] } ]

[]

[]

[ { "id": "PMID-10228008__text", "type": "abstract", "text": [ "The evolutionarily conserved sequence upstream of the human Ig heavy chain S gamma 3 region is an inducible promoter: synergistic activation by CD40 ligand and IL-4 via cooperative NF-kappa B and STAT-6 binding sites. \nGermline C gamma gene transcription is a crucial event in the process that leads to switch DNA recombination to IgG, but its regulation in the human is poorly understood. We took advantage of our monoclonal model of germinal center B cell differentiation, IgM+ IgD+ CL-01 cells, to define the role of the I gamma 3 evolutionarily conserved sequence (ECS) in the germline transcriptional activation of the human C gamma 3 gene. The I gamma 3 ECS lies upstream of the major I gamma 3 transcription initiation site and displays more than 90% identity with the corresponding human I gamma 1, I gamma 2, and I gamma 4 regions. Reporter luciferase gene vectors containing the human gamma 3 ECS were used to transfect CL-01 cells, which have been shown to undergo Smu-->S gamma 3 DNA recombination, upon engagement of CD40 by CD40 ligand (CD40L) and exposure to IL-4. In these transfected CL-01 cells, CD40:CD40L engagement and exposure to IL-4 synergistically induced gamma 3 ECS-dependent luciferase reporter gene activation. Targeted mutational analysis demonstrated that a tandem NF-kappa B/Rel binding motif is critical for the gamma 3 ECS responsiveness to both CD40L and IL-4, while a STAT-6-binding site is additionally required for IL-4 inducibility. Electrophoretic mobility shift assays showed that p50/p65/c-Rel and STAT-6 are effectively induced by CD40L and IL-4, respectively, and bind to specific DNA motifs within the ECS. These partially overlapping CD40L and IL-4 responsive elements are functionally cooperative as the disruption of one of them prevents synergistic promoter activation. Thus, the gamma 3 ECS is an inducible promoter containing cis elements that critically mediate CD40L and IL-4-triggered transcriptional activation of the human C gamma 3 gene. " ], "offsets": [ [ 0, 1995 ] ] } ]

[ { "id": "PMID-10228008_T1", "type": "Protein", "text": [ "CD40 ligand" ], "offsets": [ [ 144, 155 ] ], "normalized": [] }, { "id": "PMID-10228008_T2", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 160, 164 ] ], "normalized": [] }, { "id": "PMID-10228008_T3", "type": "Protein", "text": [ "STAT-6" ], "offsets": [ [ 196, 202 ] ], "normalized": [] }, { "id": "PMID-10228008_T4", "type": "Protein", "text": [ "I gamma 3" ], "offsets": [ [ 524, 533 ] ], "normalized": [] }, { "id": "PMID-10228008_T5", "type": "Protein", "text": [ "C gamma 3" ], "offsets": [ [ 630, 639 ] ], "normalized": [] }, { "id": "PMID-10228008_T6", "type": "Protein", "text": [ "I gamma 3" ], "offsets": [ [ 650, 659 ] ], "normalized": [] }, { "id": "PMID-10228008_T7", "type": "Protein", "text": [ "I gamma 3" ], "offsets": [ [ 691, 700 ] ], "normalized": [] }, { "id": "PMID-10228008_T8", "type": "Protein", "text": [ "I gamma 1" ], "offsets": [ [ 796, 805 ] ], "normalized": [] }, { "id": "PMID-10228008_T9", "type": "Protein", "text": [ "I gamma 2" ], "offsets": [ [ 807, 816 ] ], "normalized": [] }, { "id": "PMID-10228008_T10", "type": "Protein", "text": [ "I gamma 4" ], "offsets": [ [ 822, 831 ] ], "normalized": [] }, { "id": "PMID-10228008_T11", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 1030, 1034 ] ], "normalized": [] }, { "id": "PMID-10228008_T12", "type": "Protein", "text": [ "CD40 ligand" ], "offsets": [ [ 1038, 1049 ] ], "normalized": [] }, { "id": "PMID-10228008_T13", "type": "Protein", "text": [ "CD40L" ], "offsets": [ [ 1051, 1056 ] ], "normalized": [] }, { "id": "PMID-10228008_T14", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1074, 1078 ] ], "normalized": [] }, { "id": "PMID-10228008_T15", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 1114, 1118 ] ], "normalized": [] }, { "id": "PMID-10228008_T16", "type": "Protein", "text": [ "CD40L" ], "offsets": [ [ 1119, 1124 ] ], "normalized": [] }, { "id": "PMID-10228008_T17", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1152, 1156 ] ], "normalized": [] }, { "id": "PMID-10228008_T18", "type": "Protein", "text": [ "CD40L" ], "offsets": [ [ 1380, 1385 ] ], "normalized": [] }, { "id": "PMID-10228008_T19", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1390, 1394 ] ], "normalized": [] }, { "id": "PMID-10228008_T20", "type": "Protein", "text": [ "STAT-6" ], "offsets": [ [ 1404, 1410 ] ], "normalized": [] }, { "id": "PMID-10228008_T21", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1453, 1457 ] ], "normalized": [] }, { "id": "PMID-10228008_T22", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1522, 1525 ] ], "normalized": [] }, { "id": "PMID-10228008_T23", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1526, 1529 ] ], "normalized": [] }, { "id": "PMID-10228008_T24", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 1530, 1535 ] ], "normalized": [] }, { "id": "PMID-10228008_T25", "type": "Protein", "text": [ "STAT-6" ], "offsets": [ [ 1540, 1546 ] ], "normalized": [] }, { "id": "PMID-10228008_T26", "type": "Protein", "text": [ "CD40L" ], "offsets": [ [ 1574, 1579 ] ], "normalized": [] }, { "id": "PMID-10228008_T27", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1584, 1588 ] ], "normalized": [] }, { "id": "PMID-10228008_T28", "type": "Protein", "text": [ "CD40L" ], "offsets": [ [ 1680, 1685 ] ], "normalized": [] }, { "id": "PMID-10228008_T29", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1690, 1694 ] ], "normalized": [] }, { "id": "PMID-10228008_T30", "type": "Protein", "text": [ "CD40L" ], "offsets": [ [ 1914, 1919 ] ], "normalized": [] }, { "id": "PMID-10228008_T31", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1924, 1928 ] ], "normalized": [] } ]

[ { "id": "PMID-10228008_E1", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 512, 516 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228008_E2" } ] }, { "id": "PMID-10228008_E2", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 606, 616 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228008_T5" } ] }, { "id": "PMID-10228008_E3", "type": "Binding", "trigger": { "text": [ "engagement" ], "offsets": [ [ 1016, 1026 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228008_T11" }, { "role": "Theme", "ref_id": "PMID-10228008_T12" } ] }, { "id": "PMID-10228008_E4", "type": "Binding", "trigger": { "text": [ "engagement" ], "offsets": [ [ 1125, 1135 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228008_T15" }, { "role": "Theme", "ref_id": "PMID-10228008_T16" } ] }, { "id": "PMID-10228008_E5", "type": "Positive_regulation", "trigger": { "text": [ "inducibility" ], "offsets": [ [ 1458, 1470 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228008_T21" } ] }, { "id": "PMID-10228008_E6", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1563, 1570 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228008_T24" }, { "role": "Cause", "ref_id": "PMID-10228008_T26" } ] }, { "id": "PMID-10228008_E7", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1563, 1570 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228008_T23" }, { "role": "Cause", "ref_id": "PMID-10228008_T26" } ] }, { "id": "PMID-10228008_E8", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1563, 1570 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228008_T25" }, { "role": "Cause", "ref_id": "PMID-10228008_T27" } ] }, { "id": "PMID-10228008_E9", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1563, 1570 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228008_T22" }, { "role": "Cause", "ref_id": "PMID-10228008_T26" } ] }, { "id": "PMID-10228008_E10", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 1608, 1612 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228008_T24" } ] }, { "id": "PMID-10228008_E11", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 1608, 1612 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228008_T23" } ] }, { "id": "PMID-10228008_E12", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 1608, 1612 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228008_T22" } ] }, { "id": "PMID-10228008_E13", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 1608, 1612 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228008_T25" } ] } ]

[ { "id": "PMID-10228008_1", "entity_ids": [ "PMID-10228008_T12", "PMID-10228008_T13" ] } ]

[]

[ { "id": "PMID-10228026__text", "type": "abstract", "text": [ "Thrombin-induced p65 homodimer binding to downstream NF-kappa B site of the promoter mediates endothelial ICAM-1 expression and neutrophil adhesion. \nWe investigated the mechanisms by which proinflammatory mediator, thrombin, released during intravascular coagulation and tissue injury, induces ICAM-1 (CD54) expression in endothelial cells. Stimulation of HUVEC with thrombin resulted in dose- and time-dependent increases in ICAM-1 mRNA and cell surface expression and in ICAM-1-dependent endothelial adhesivity toward polymorphonuclear leukocytes. Transient transfection of endothelial cells with ICAM-1 promoter luciferase reporter gene (ICAM-1LUC) constructs indicated that deletion of upstream NF-kappa B site (-533 bases from translation start site) had no effect on thrombin responsiveness, whereas mutation/deletion of downstream NF-kappa B site (-223 bases from the translation start site) prevented the activation of ICAM-1 promoter, indicating that the downstream NF-kappa B site is critical for thrombin inducibility. NF-kappa B-directed luciferase activity increased approximately 3-fold when cells transfected with the plasmid pNF-kappa BLUC containing five copies of consensus NF-kappa B site linked to a minimal adenovirus E1B promoter-luciferase gene were exposed to thrombin, indicating that activation of NF-kappa B was essential for thrombin response. Gel supershift assays demonstrated that thrombin induced binding of NF-kappa Bp65 (Rel A) to downstream NF-kappa B site of the ICAM-1 promoter. Thrombin receptor activation peptide, a 14-amino-acid peptide representing the new NH2 terminus of proteolytically activated receptor-1, mimicked thrombin's action in inducing ICAM-1 expression. These data indicate that thrombin activates endothelial ICAM-1 expression and polymorphonuclear leukocyte adhesion by NF-kappa Bp65 binding to the downstream NF-kappa B site of ICAM-1 promoter after proteolytically activated receptor-1 activation. " ], "offsets": [ [ 0, 1960 ] ] } ]

[ { "id": "PMID-10228026_T1", "type": "Protein", "text": [ "Thrombin" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "PMID-10228026_T2", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 17, 20 ] ], "normalized": [] }, { "id": "PMID-10228026_T3", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 106, 112 ] ], "normalized": [] }, { "id": "PMID-10228026_T4", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 216, 224 ] ], "normalized": [] }, { "id": "PMID-10228026_T5", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 295, 301 ] ], "normalized": [] }, { "id": "PMID-10228026_T6", "type": "Protein", "text": [ "CD54" ], "offsets": [ [ 303, 307 ] ], "normalized": [] }, { "id": "PMID-10228026_T7", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 368, 376 ] ], "normalized": [] }, { "id": "PMID-10228026_T8", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 427, 433 ] ], "normalized": [] }, { "id": "PMID-10228026_T9", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 474, 480 ] ], "normalized": [] }, { "id": "PMID-10228026_T10", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 600, 606 ] ], "normalized": [] }, { "id": "PMID-10228026_T11", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 774, 782 ] ], "normalized": [] }, { "id": "PMID-10228026_T12", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 928, 934 ] ], "normalized": [] }, { "id": "PMID-10228026_T13", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1008, 1016 ] ], "normalized": [] }, { "id": "PMID-10228026_T14", "type": "Protein", "text": [ "E1B" ], "offsets": [ [ 1240, 1243 ] ], "normalized": [] }, { "id": "PMID-10228026_T15", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1285, 1293 ] ], "normalized": [] }, { "id": "PMID-10228026_T16", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1354, 1362 ] ], "normalized": [] }, { "id": "PMID-10228026_T17", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1413, 1421 ] ], "normalized": [] }, { "id": "PMID-10228026_T18", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1451, 1454 ] ], "normalized": [] }, { "id": "PMID-10228026_T19", "type": "Protein", "text": [ "Rel A" ], "offsets": [ [ 1456, 1461 ] ], "normalized": [] }, { "id": "PMID-10228026_T20", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 1500, 1506 ] ], "normalized": [] }, { "id": "PMID-10228026_T21", "type": "Protein", "text": [ "Thrombin receptor" ], "offsets": [ [ 1517, 1534 ] ], "normalized": [] }, { "id": "PMID-10228026_T22", "type": "Protein", "text": [ "proteolytically activated receptor-1" ], "offsets": [ [ 1616, 1652 ] ], "normalized": [] }, { "id": "PMID-10228026_T23", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1663, 1671 ] ], "normalized": [] }, { "id": "PMID-10228026_T24", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 1693, 1699 ] ], "normalized": [] }, { "id": "PMID-10228026_T25", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1737, 1745 ] ], "normalized": [] }, { "id": "PMID-10228026_T26", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 1768, 1774 ] ], "normalized": [] }, { "id": "PMID-10228026_T27", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1840, 1843 ] ], "normalized": [] }, { "id": "PMID-10228026_T28", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 1889, 1895 ] ], "normalized": [] }, { "id": "PMID-10228026_T29", "type": "Protein", "text": [ "proteolytically activated receptor-1" ], "offsets": [ [ 1911, 1947 ] ], "normalized": [] }, { "id": "PMID-10228026_T41", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 935, 943 ] ], "normalized": [] }, { "id": "PMID-10228026_T44", "type": "Entity", "text": [ "downstream NF-kappa B site" ], "offsets": [ [ 1466, 1492 ] ], "normalized": [] }, { "id": "PMID-10228026_T50", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1896, 1904 ] ], "normalized": [] } ]

[ { "id": "PMID-10228026_E1", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 9, 16 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_E2" }, { "role": "Cause", "ref_id": "PMID-10228026_T1" } ] }, { "id": "PMID-10228026_E2", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 31, 38 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_T2" } ] }, { "id": "PMID-10228026_E3", "type": "Positive_regulation", "trigger": { "text": [ "mediates" ], "offsets": [ [ 85, 93 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_E4" }, { "role": "Cause", "ref_id": "PMID-10228026_E1" } ] }, { "id": "PMID-10228026_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 113, 123 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_T3" } ] }, { "id": "PMID-10228026_E5", "type": "Localization", "trigger": { "text": [ "released" ], "offsets": [ [ 226, 234 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_T4" } ] }, { "id": "PMID-10228026_E6", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 287, 294 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_E7" }, { "role": "Cause", "ref_id": "PMID-10228026_T4" } ] }, { "id": "PMID-10228026_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 309, 319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_T5" } ] }, { "id": "PMID-10228026_E8", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 414, 423 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_E10" } ] }, { "id": "PMID-10228026_E9", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 414, 423 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_T8" } ] }, { "id": "PMID-10228026_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 456, 466 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_T8" } ] }, { "id": "PMID-10228026_E11", "type": "Negative_regulation", "trigger": { "text": [ "prevented" ], "offsets": [ [ 900, 909 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_E12" } ] }, { "id": "PMID-10228026_E12", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 914, 924 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_T12" }, { "role": "Site", "ref_id": "PMID-10228026_T41" } ] }, { "id": "PMID-10228026_E13", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1422, 1429 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_E14" }, { "role": "Cause", "ref_id": "PMID-10228026_T17" } ] }, { "id": "PMID-10228026_E14", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1430, 1437 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_T19" }, { "role": "Theme", "ref_id": "PMID-10228026_T20" }, { "role": "Site", "ref_id": "PMID-10228026_T44" } ] }, { "id": "PMID-10228026_E15", "type": "Positive_regulation", "trigger": { "text": [ "inducing" ], "offsets": [ [ 1684, 1692 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_E17" } ] }, { "id": "PMID-10228026_E16", "type": "Positive_regulation", "trigger": { "text": [ "inducing" ], "offsets": [ [ 1684, 1692 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_E17" }, { "role": "Cause", "ref_id": "PMID-10228026_T23" } ] }, { "id": "PMID-10228026_E17", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1700, 1710 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_T24" } ] }, { "id": "PMID-10228026_E18", "type": "Positive_regulation", "trigger": { "text": [ "activates" ], "offsets": [ [ 1746, 1755 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_E19" }, { "role": "Cause", "ref_id": "PMID-10228026_T25" } ] }, { "id": "PMID-10228026_E19", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1775, 1785 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_T26" } ] }, { "id": "PMID-10228026_E20", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1844, 1851 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_T27" }, { "role": "Theme", "ref_id": "PMID-10228026_T28" }, { "role": "Site", "ref_id": "PMID-10228026_T50" } ] }, { "id": "PMID-10228026_E21", "type": "Positive_regulation", "trigger": { "text": [ "after" ], "offsets": [ [ 1905, 1910 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_E20" }, { "role": "Cause", "ref_id": "PMID-10228026_E22" } ] }, { "id": "PMID-10228026_E22", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1948, 1958 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10228026_T29" } ] } ]

[ { "id": "PMID-10228026_1", "entity_ids": [ "PMID-10228026_T5", "PMID-10228026_T6" ] }, { "id": "PMID-10228026_2", "entity_ids": [ "PMID-10228026_T19", "PMID-10228026_T18" ] } ]

[]

[ { "id": "PMID-10229815__text", "type": "abstract", "text": [ "CTLA-4-Mediated inhibition of early events of T cell proliferation. \nCTLA-4 engagement by mAbs inhibits, while CD28 enhances, IL-2 production and proliferation upon T cell activation. Here, we have analyzed the mechanisms involved in CTLA-4-mediated inhibition of T cell activation of naive CD4+ T cells using Ab cross-linking. CTLA-4 ligation inhibited CD3/CD28-induced IL-2 mRNA accumulation by inhibiting IL-2 transcription, which appears to be mediated in part through decreasing NF-AT accumulation in the nuclei. However, CTLA-4 ligation did not appear to affect the CD28-mediated stabilization of IL-2 mRNA. Further, CTLA-4 engagement inhibited progression through the cell cycle by inhibiting the production of cyclin D3, cyclin-dependent kinase (cdk)4, and cdk6 when the T cells were stimulated with anti-CD3/CD28 and with anti-CD3 alone. These results indicate that CTLA-4 signaling inhibits events early in T cell activation both at IL-2 transcription and at the level of IL-2-independent events of the cell cycle, and does not simply oppose CD28-mediated costimulation. " ], "offsets": [ [ 0, 1081 ] ] } ]

[ { "id": "PMID-10229815_T1", "type": "Protein", "text": [ "CTLA-4" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "PMID-10229815_T2", "type": "Protein", "text": [ "CTLA-4" ], "offsets": [ [ 69, 75 ] ], "normalized": [] }, { "id": "PMID-10229815_T3", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 111, 115 ] ], "normalized": [] }, { "id": "PMID-10229815_T4", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 126, 130 ] ], "normalized": [] }, { "id": "PMID-10229815_T5", "type": "Protein", "text": [ "CTLA-4" ], "offsets": [ [ 234, 240 ] ], "normalized": [] }, { "id": "PMID-10229815_T6", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 291, 294 ] ], "normalized": [] }, { "id": "PMID-10229815_T7", "type": "Protein", "text": [ "CTLA-4" ], "offsets": [ [ 328, 334 ] ], "normalized": [] }, { "id": "PMID-10229815_T8", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 358, 362 ] ], "normalized": [] }, { "id": "PMID-10229815_T9", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 371, 375 ] ], "normalized": [] }, { "id": "PMID-10229815_T10", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 408, 412 ] ], "normalized": [] }, { "id": "PMID-10229815_T11", "type": "Protein", "text": [ "CTLA-4" ], "offsets": [ [ 527, 533 ] ], "normalized": [] }, { "id": "PMID-10229815_T12", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 572, 576 ] ], "normalized": [] }, { "id": "PMID-10229815_T13", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 603, 607 ] ], "normalized": [] }, { "id": "PMID-10229815_T14", "type": "Protein", "text": [ "CTLA-4" ], "offsets": [ [ 623, 629 ] ], "normalized": [] }, { "id": "PMID-10229815_T15", "type": "Protein", "text": [ "cyclin D3" ], "offsets": [ [ 718, 727 ] ], "normalized": [] }, { "id": "PMID-10229815_T16", "type": "Protein", "text": [ "(cdk)4" ], "offsets": [ [ 753, 759 ] ], "normalized": [] }, { "id": "PMID-10229815_T17", "type": "Protein", "text": [ "cdk6" ], "offsets": [ [ 765, 769 ] ], "normalized": [] }, { "id": "PMID-10229815_T18", "type": "Protein", "text": [ "CTLA-4" ], "offsets": [ [ 875, 881 ] ], "normalized": [] }, { "id": "PMID-10229815_T19", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 943, 947 ] ], "normalized": [] }, { "id": "PMID-10229815_T20", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 982, 986 ] ], "normalized": [] }, { "id": "PMID-10229815_T21", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 1052, 1056 ] ], "normalized": [] } ]

[ { "id": "PMID-10229815_E1", "type": "Binding", "trigger": { "text": [ "engagement" ], "offsets": [ [ 76, 86 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_T2" } ] }, { "id": "PMID-10229815_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 95, 103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_E5" }, { "role": "Cause", "ref_id": "PMID-10229815_E1" } ] }, { "id": "PMID-10229815_E3", "type": "Positive_regulation", "trigger": { "text": [ "enhances" ], "offsets": [ [ 116, 124 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_E5" }, { "role": "Cause", "ref_id": "PMID-10229815_T3" } ] }, { "id": "PMID-10229815_E4", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 131, 141 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_T4" } ] }, { "id": "PMID-10229815_E5", "type": "Positive_regulation", "trigger": { "text": [ "upon" ], "offsets": [ [ 160, 164 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_E4" } ] }, { "id": "PMID-10229815_E6", "type": "Binding", "trigger": { "text": [ "ligation" ], "offsets": [ [ 335, 343 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_T7" } ] }, { "id": "PMID-10229815_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 344, 353 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_E8" }, { "role": "Cause", "ref_id": "PMID-10229815_E9" } ] }, { "id": "PMID-10229815_E8", "type": "Positive_regulation", "trigger": { "text": [ "accumulation" ], "offsets": [ [ 381, 393 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_T9" }, { "role": "Cause", "ref_id": "PMID-10229815_T8" } ] }, { "id": "PMID-10229815_E9", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 397, 407 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_E10" }, { "role": "Cause", "ref_id": "PMID-10229815_E6" } ] }, { "id": "PMID-10229815_E10", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 413, 426 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_T10" } ] }, { "id": "PMID-10229815_E11", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 448, 456 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_E9" } ] }, { "id": "PMID-10229815_E12", "type": "Binding", "trigger": { "text": [ "ligation" ], "offsets": [ [ 534, 542 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_T11" } ] }, { "id": "PMID-10229815_E13", "type": "Regulation", "trigger": { "text": [ "affect" ], "offsets": [ [ 561, 567 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_E14" }, { "role": "Cause", "ref_id": "PMID-10229815_E12" } ] }, { "id": "PMID-10229815_E14", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 577, 585 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_E15" }, { "role": "Cause", "ref_id": "PMID-10229815_T12" } ] }, { "id": "PMID-10229815_E15", "type": "Positive_regulation", "trigger": { "text": [ "stabilization" ], "offsets": [ [ 586, 599 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_T13" } ] }, { "id": "PMID-10229815_E16", "type": "Binding", "trigger": { "text": [ "engagement" ], "offsets": [ [ 630, 640 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_T14" } ] }, { "id": "PMID-10229815_E17", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 689, 699 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_E21" }, { "role": "Cause", "ref_id": "PMID-10229815_E16" } ] }, { "id": "PMID-10229815_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 689, 699 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_E20" }, { "role": "Cause", "ref_id": "PMID-10229815_E16" } ] }, { "id": "PMID-10229815_E19", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 689, 699 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_E22" }, { "role": "Cause", "ref_id": "PMID-10229815_E16" } ] }, { "id": "PMID-10229815_E20", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 704, 714 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_T17" } ] }, { "id": "PMID-10229815_E21", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 704, 714 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_T15" } ] }, { "id": "PMID-10229815_E22", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 704, 714 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_T16" } ] }, { "id": "PMID-10229815_E23", "type": "Positive_regulation", "trigger": { "text": [ "when" ], "offsets": [ [ 770, 774 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_E22" } ] }, { "id": "PMID-10229815_E24", "type": "Positive_regulation", "trigger": { "text": [ "when" ], "offsets": [ [ 770, 774 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_E21" } ] }, { "id": "PMID-10229815_E25", "type": "Positive_regulation", "trigger": { "text": [ "when" ], "offsets": [ [ 770, 774 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_E20" } ] }, { "id": "PMID-10229815_E26", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 892, 900 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_E27" } ] }, { "id": "PMID-10229815_E27", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 948, 961 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229815_T19" } ] } ]

[]

[]

[ { "id": "PMID-10229820__text", "type": "abstract", "text": [ "Fibroblast growth factor-1 (FGF-1) enhances IL-2 production and nuclear translocation of NF-kappaB in FGF receptor-bearing Jurkat T cells. \nFibroblast growth factors (FGFs) are heparin-binding proteins crucial to embryogenesis, angiogenesis, and wound healing. FGF-1 is abundantly expressed in the synovium in rheumatoid arthritis and in rejecting allografts, sites of chronic immune-mediated inflammation. The frequency of FGF-1-responsive T cells is increased in the peripheral blood of these disorders, and a high percentage of infiltrating T cells in rheumatoid arthritis synovium express receptors for FGF-1. To understand the action of FGF-1 in T cells, studies were initiated in Jurkat T cells that express the signaling isoform of FGF receptor-1. These experiments show that FGF-1 stimulation of Jurkat T cells provides a second signal that augments TCR-mediated IL-2 production. Analogous to costimulation via CD28, this activity is mediated through activation of Rel/kappaB, a family of transcription factors known to regulate IL-2 and other activation-inducible proteins. FGF-1 alone induces modest nuclear translocation of kappaB-binding proteins, and this translocation is enhanced by the combination of anti-CD3 and FGF-1. This NF-kappaB binding complex is composed of transcriptionally active p65(RelA)/p50 heterodimers and results primarily from the targeted degradation of IkappaB-alpha, an inhibitor that sequesters Rel/kappaB in the cytoplasm. These data are the first to show a connection between FGF-1 signaling and NF-kappaB activation outside of embryonic development. The signaling events that link FGF receptor-1 engagement and NF-kappaB activation in Jurkat are probably distinct from the CD28 costimulation pathway, since FGF-1-induced Rel/kappaB binding proteins do not contain significant levels of c-Rel and are not identical with the CD28 response complex. " ], "offsets": [ [ 0, 1888 ] ] } ]

[ { "id": "PMID-10229820_T1", "type": "Protein", "text": [ "Fibroblast growth factor-1" ], "offsets": [ [ 0, 26 ] ], "normalized": [] }, { "id": "PMID-10229820_T2", "type": "Protein", "text": [ "FGF-1" ], "offsets": [ [ 28, 33 ] ], "normalized": [] }, { "id": "PMID-10229820_T3", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 44, 48 ] ], "normalized": [] }, { "id": "PMID-10229820_T4", "type": "Protein", "text": [ "FGF-1" ], "offsets": [ [ 261, 266 ] ], "normalized": [] }, { "id": "PMID-10229820_T5", "type": "Protein", "text": [ "FGF-1" ], "offsets": [ [ 424, 429 ] ], "normalized": [] }, { "id": "PMID-10229820_T6", "type": "Protein", "text": [ "FGF-1" ], "offsets": [ [ 607, 612 ] ], "normalized": [] }, { "id": "PMID-10229820_T7", "type": "Protein", "text": [ "FGF-1" ], "offsets": [ [ 642, 647 ] ], "normalized": [] }, { "id": "PMID-10229820_T8", "type": "Protein", "text": [ "FGF receptor-1" ], "offsets": [ [ 739, 753 ] ], "normalized": [] }, { "id": "PMID-10229820_T9", "type": "Protein", "text": [ "FGF-1" ], "offsets": [ [ 783, 788 ] ], "normalized": [] }, { "id": "PMID-10229820_T10", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 871, 875 ] ], "normalized": [] }, { "id": "PMID-10229820_T11", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 919, 923 ] ], "normalized": [] }, { "id": "PMID-10229820_T12", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1037, 1041 ] ], "normalized": [] }, { "id": "PMID-10229820_T13", "type": "Protein", "text": [ "FGF-1" ], "offsets": [ [ 1083, 1088 ] ], "normalized": [] }, { "id": "PMID-10229820_T14", "type": "Protein", "text": [ "FGF-1" ], "offsets": [ [ 1230, 1235 ] ], "normalized": [] }, { "id": "PMID-10229820_T15", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1308, 1311 ] ], "normalized": [] }, { "id": "PMID-10229820_T16", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 1312, 1316 ] ], "normalized": [] }, { "id": "PMID-10229820_T17", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1318, 1321 ] ], "normalized": [] }, { "id": "PMID-10229820_T18", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1390, 1403 ] ], "normalized": [] }, { "id": "PMID-10229820_T19", "type": "Protein", "text": [ "FGF-1" ], "offsets": [ [ 1517, 1522 ] ], "normalized": [] }, { "id": "PMID-10229820_T20", "type": "Protein", "text": [ "FGF receptor-1" ], "offsets": [ [ 1623, 1637 ] ], "normalized": [] }, { "id": "PMID-10229820_T21", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 1715, 1719 ] ], "normalized": [] }, { "id": "PMID-10229820_T22", "type": "Protein", "text": [ "FGF-1" ], "offsets": [ [ 1749, 1754 ] ], "normalized": [] }, { "id": "PMID-10229820_T23", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 1828, 1833 ] ], "normalized": [] }, { "id": "PMID-10229820_T24", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 1865, 1869 ] ], "normalized": [] } ]

[ { "id": "PMID-10229820_E1", "type": "Positive_regulation", "trigger": { "text": [ "enhances" ], "offsets": [ [ 35, 43 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_E2" }, { "role": "Cause", "ref_id": "PMID-10229820_T2" } ] }, { "id": "PMID-10229820_E2", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 49, 59 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_T3" } ] }, { "id": "PMID-10229820_E3", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 281, 290 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_T4" } ] }, { "id": "PMID-10229820_E4", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 706, 713 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_T8" } ] }, { "id": "PMID-10229820_E5", "type": "Positive_regulation", "trigger": { "text": [ "provides" ], "offsets": [ [ 819, 827 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_E6" } ] }, { "id": "PMID-10229820_E6", "type": "Positive_regulation", "trigger": { "text": [ "augments" ], "offsets": [ [ 849, 857 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_E7" } ] }, { "id": "PMID-10229820_E7", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 862, 870 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_E8" } ] }, { "id": "PMID-10229820_E8", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 876, 886 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_T10" } ] }, { "id": "PMID-10229820_E9", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 942, 950 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_E5" } ] }, { "id": "PMID-10229820_E10", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 1028, 1036 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_T12" } ] }, { "id": "PMID-10229820_E11", "type": "Positive_regulation", "trigger": { "text": [ "composed" ], "offsets": [ [ 1271, 1279 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_T15" } ] }, { "id": "PMID-10229820_E12", "type": "Positive_regulation", "trigger": { "text": [ "composed" ], "offsets": [ [ 1271, 1279 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_T16" } ] }, { "id": "PMID-10229820_E13", "type": "Positive_regulation", "trigger": { "text": [ "composed" ], "offsets": [ [ 1271, 1279 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_T17" } ] }, { "id": "PMID-10229820_E14", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 1339, 1346 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_E13" }, { "role": "Cause", "ref_id": "PMID-10229820_E17" } ] }, { "id": "PMID-10229820_E15", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 1339, 1346 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_E11" }, { "role": "Cause", "ref_id": "PMID-10229820_E17" } ] }, { "id": "PMID-10229820_E16", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 1339, 1346 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_E12" }, { "role": "Cause", "ref_id": "PMID-10229820_E17" } ] }, { "id": "PMID-10229820_E17", "type": "Protein_catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1375, 1386 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_T18" } ] }, { "id": "PMID-10229820_E18", "type": "Binding", "trigger": { "text": [ "engagement" ], "offsets": [ [ 1638, 1648 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_T20" } ] }, { "id": "PMID-10229820_E19", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1755, 1762 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229820_T23" }, { "role": "Cause", "ref_id": "PMID-10229820_T22" } ] } ]

[ { "id": "PMID-10229820_1", "entity_ids": [ "PMID-10229820_T2", "PMID-10229820_T1" ] } ]

[]

[ { "id": "PMID-10229841__text", "type": "abstract", "text": [ "Signaling through the lymphotoxin-beta receptor stimulates HIV-1 replication alone and in cooperation with soluble or membrane-bound TNF-alpha. \nThe level of ongoing HIV-1 replication within an individual is critical to HIV-1 pathogenesis. Among host immune factors, the cytokine TNF-alpha has previously been shown to increase HIV-1 replication in various monocyte and T cell model systems. Here, we demonstrate that signaling through the TNF receptor family member, the lymphotoxin-beta (LT-beta) receptor (LT-betaR), also regulates HIV-1 replication. Furthermore, HIV-1 replication is cooperatively stimulated when the distinct LT-betaR and TNF receptor systems are simultaneously engaged by their specific ligands. Moreover, in a physiological coculture cellular assay system, we show that membrane-bound TNF-alpha and LT-alpha1beta2 act virtually identically to their soluble forms in the regulation of HIV-1 replication. Thus, cosignaling via the LT-beta and TNF-alpha receptors is probably involved in the modulation of HIV-1 replication and the subsequent determination of HIV-1 viral burden in monocytes. Intriguingly, surface expression of LT-alpha1beta2 is up-regulated on a T cell line acutely infected with HIV-1, suggesting a positive feedback loop between HIV-1 infection, LT-alpha1beta2 expression, and HIV-1 replication. Given the critical role that LT-alpha1beta2 plays in lymphoid architecture, we speculate that LT-alpha1beta2 may be involved in HIV-associated abnormalities of the lymphoid organs. " ], "offsets": [ [ 0, 1519 ] ] } ]

[ { "id": "PMID-10229841_T1", "type": "Protein", "text": [ "lymphotoxin-beta receptor" ], "offsets": [ [ 22, 47 ] ], "normalized": [] }, { "id": "PMID-10229841_T2", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 133, 142 ] ], "normalized": [] }, { "id": "PMID-10229841_T3", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 280, 289 ] ], "normalized": [] }, { "id": "PMID-10229841_T4", "type": "Protein", "text": [ "lymphotoxin-beta (LT-beta) receptor" ], "offsets": [ [ 472, 507 ] ], "normalized": [] }, { "id": "PMID-10229841_T5", "type": "Protein", "text": [ "LT-betaR" ], "offsets": [ [ 509, 517 ] ], "normalized": [] }, { "id": "PMID-10229841_T6", "type": "Protein", "text": [ "LT-betaR" ], "offsets": [ [ 631, 639 ] ], "normalized": [] }, { "id": "PMID-10229841_T7", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 809, 818 ] ], "normalized": [] }, { "id": "PMID-10229841_T8", "type": "Protein", "text": [ "LT-beta" ], "offsets": [ [ 953, 960 ] ], "normalized": [] }, { "id": "PMID-10229841_T9", "type": "Protein", "text": [ "TNF-alpha receptors" ], "offsets": [ [ 965, 984 ] ], "normalized": [] } ]

[ { "id": "PMID-10229841_E1", "type": "Binding", "trigger": { "text": [ "simultaneously engaged" ], "offsets": [ [ 669, 691 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10229841_T6" } ] } ]

[ { "id": "PMID-10229841_1", "entity_ids": [ "PMID-10229841_T4", "PMID-10229841_T5" ] } ]

[]

[ { "id": "PMID-10232385__text", "type": "abstract", "text": [ "Resistance to tumor necrosis factor induced apoptosis in vitro correlates with high metastatic capacity of cells in vivo. \nTNF is one of the cytokines secreted by the cells of the immune system. Our data demonstrate that those cell lines lacking capability to form metastatic tumors in vivo are susceptible to TNF induced apoptosis in vitro. However, cell lines with high metastatic potential are resistant to TNF in vitro. Furthermore, the same cell lines were resistant to cytolytic action of other cytotoxic proteins secreted by LAK cells. Our data showed that TNF resistance in vitro correlates with the increased level of transcription factor NF-kappaB. This finding may provide a tool to improve current protocols of immunotherapy and insights to how tumor cells are or are not killed by LAK cells. " ], "offsets": [ [ 0, 805 ] ] } ]

[]

[]

[]

[]

[ { "id": "PMID-10233875__text", "type": "abstract", "text": [ "NF-kappaB activation is required for C5a-induced interleukin-8 gene expression in mononuclear cells. \nC5a, a potent peptide chemoattractant, stimulates interleukin-8 (IL-8) secretion from peripheral blood mononuclear cells (PBMC). Experiments were conducted to understand the mechanisms for C5a-induced IL-8 production, which was 14-fold greater than that in unstimulated cells by 2 hours. IL-8 secretion was accompanied by accumulation of IL-8 mRNA in the cytosol and by nuclear expression of a kappaB DNA binding activity within 30 minutes. AP-1 but not NF-IL-6 DNA binding activity was also detected in C5a-stimulated PBMC; however, its delayed expression (maximal at 4 hours) suggested a less important role in the rapid production of IL-8. The correlation between C5a-induced kappaB binding activity and IL-8 gene expression was examined in the RAW264.7 macrophage cells using reporter genes directed by the kappaB sequence from IkappaBalpha and IL-8 promoter regions. C5a-induced reporter gene expression was abolished by introducing mutations into the kappaB sites and by coexpression of a dominant negative IkappaBalpha construct resistant to agonist-induced phosphorylation. Pertussis toxin, which ADP-ribosylates the Gi proteins known to couple to the C5a receptor, produced minimal inhibition of C5a-induced IL-8 expression and had little effect on C5a-induced calcium mobilization in RAW264.7 cells. These results suggest that NF-kappaB activation is required for C5a-induced IL-8 gene expression and that this response is mediated primarily through a pertussis toxin-insensitive pathway. " ], "offsets": [ [ 0, 1601 ] ] } ]

[ { "id": "PMID-10233875_T1", "type": "Protein", "text": [ "interleukin-8" ], "offsets": [ [ 49, 62 ] ], "normalized": [] }, { "id": "PMID-10233875_T2", "type": "Protein", "text": [ "interleukin-8" ], "offsets": [ [ 152, 165 ] ], "normalized": [] }, { "id": "PMID-10233875_T3", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 167, 171 ] ], "normalized": [] }, { "id": "PMID-10233875_T4", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 303, 307 ] ], "normalized": [] }, { "id": "PMID-10233875_T5", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 390, 394 ] ], "normalized": [] }, { "id": "PMID-10233875_T6", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 440, 444 ] ], "normalized": [] }, { "id": "PMID-10233875_T7", "type": "Protein", "text": [ "NF-IL-6" ], "offsets": [ [ 556, 563 ] ], "normalized": [] }, { "id": "PMID-10233875_T8", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 739, 743 ] ], "normalized": [] }, { "id": "PMID-10233875_T9", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 809, 813 ] ], "normalized": [] }, { "id": "PMID-10233875_T10", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 934, 946 ] ], "normalized": [] }, { "id": "PMID-10233875_T11", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 951, 955 ] ], "normalized": [] }, { "id": "PMID-10233875_T12", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 1115, 1127 ] ], "normalized": [] }, { "id": "PMID-10233875_T13", "type": "Protein", "text": [ "C5a receptor" ], "offsets": [ [ 1262, 1274 ] ], "normalized": [] }, { "id": "PMID-10233875_T14", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 1319, 1323 ] ], "normalized": [] }, { "id": "PMID-10233875_T15", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 1488, 1492 ] ], "normalized": [] } ]

[ { "id": "PMID-10233875_E1", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 41, 48 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_E2" } ] }, { "id": "PMID-10233875_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 68, 78 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_T1" } ] }, { "id": "PMID-10233875_E3", "type": "Positive_regulation", "trigger": { "text": [ "stimulates" ], "offsets": [ [ 141, 151 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_E4" } ] }, { "id": "PMID-10233875_E4", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 173, 182 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_T3" } ] }, { "id": "PMID-10233875_E5", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 295, 302 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_E6" } ] }, { "id": "PMID-10233875_E6", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 308, 318 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_T4" } ] }, { "id": "PMID-10233875_E7", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 395, 404 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_T5" } ] }, { "id": "PMID-10233875_E8", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 568, 575 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_T7" } ] }, { "id": "PMID-10233875_E9", "type": "Positive_regulation", "trigger": { "text": [ "detected" ], "offsets": [ [ 594, 602 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_E8" } ] }, { "id": "PMID-10233875_E10", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 707, 711 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_E11" } ] }, { "id": "PMID-10233875_E11", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 725, 735 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_T8" } ] }, { "id": "PMID-10233875_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 819, 829 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_T9" } ] }, { "id": "PMID-10233875_E13", "type": "Gene_expression", "trigger": { "text": [ "coexpression" ], "offsets": [ [ 1079, 1091 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_T12" } ] }, { "id": "PMID-10233875_E14", "type": "Binding", "trigger": { "text": [ "couple" ], "offsets": [ [ 1248, 1254 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_T13" } ] }, { "id": "PMID-10233875_E15", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1293, 1303 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_E16" } ] }, { "id": "PMID-10233875_E16", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1311, 1318 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_E17" } ] }, { "id": "PMID-10233875_E17", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1324, 1334 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_T14" } ] }, { "id": "PMID-10233875_E18", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1480, 1487 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_E19" } ] }, { "id": "PMID-10233875_E19", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1498, 1508 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233875_T15" } ] } ]

[ { "id": "PMID-10233875_1", "entity_ids": [ "PMID-10233875_T3", "PMID-10233875_T2" ] } ]

[]

[ { "id": "PMID-10233879__text", "type": "abstract", "text": [ "Transcriptional targeting of retroviral vectors to the erythroblastic progeny of transduced hematopoietic stem cells. \nTargeted expression to specific tissues or cell lineages is a necessary feature of a gene therapy vector for many clinical applications, such as correction of hemoglobinopathies or thalassemias by transplantation of genetically modified hematopoietic stem cells. We developed retroviral vectors in which the constitutive viral enhancer in the U3 region of the 3' LTR is replaced by an autoregulatory enhancer of the erythroid-specific GATA-1 transcription factor gene. The replaced enhancer is propagated to the 5' LTR upon integration into the target cell genome. The modified vectors were used to transduce human hematopoietic cell lines, cord blood-derived CD34(+) stem/progenitor cells, and murine bone marrow repopulating stem cells. The expression of appropriate reporter genes (triangle upLNGFR, EGFP) was analyzed in the differentiated progeny of transduced stem cells in vitro, in liquid culture as well as in clonogenic assay, and in vivo, after bone marrow transplantation in lethally irradiated mice. The GATA-1 autoregulatory enhancer effectively restricts the expression of the LTR-driven proviral transcription unit to the erythroblastic progeny of both human progenitors and mouse-repopulating stem cells. Packaging of viral particles, integration into the target genome, and stability of the integrated provirus are not affected by the LTR modification. Enhancer replacement is therefore an effective strategy to target expression of a retroviral transgene to a specific progeny of transduced hematopoietic stem cells. " ], "offsets": [ [ 0, 1655 ] ] } ]

[ { "id": "PMID-10233879_T1", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 554, 560 ] ], "normalized": [] }, { "id": "PMID-10233879_T2", "type": "Protein", "text": [ "EGFP" ], "offsets": [ [ 922, 926 ] ], "normalized": [] }, { "id": "PMID-10233879_T3", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 1136, 1142 ] ], "normalized": [] } ]

[ { "id": "PMID-10233879_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 862, 872 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233879_T2" } ] } ]

[]

[]

[ { "id": "PMID-10233882__text", "type": "abstract", "text": [ "An essential role for NF-kappaB in human CD34(+) bone marrow cell survival. \nThe transcription factor, NF-kappaB, is important for T-cell activation, B-cell maturation, and human immunodeficiency virus transcription and plays a role in alternatively mediating and protecting against apoptosis in a variety of cell types. However, a role for NF-kappaB in human CD34(+) bone marrow cells has not been described. We provide evidence here that virtually all human CD34(+) bone marrow cells express NF-kappaB that can be activated by exposure to phorbol 12-myristate 13-acetate and a variety of cytokines, eg, tumor necrosis factor alpha, interleukin-3, and granulocyte-macrophage colony-stimulating factor. In addition, we demonstrate that NF-kappaB may be required for human CD34(+) bone marrow cell clonogenic function and survival. These results offer insight into a new role for NF-kappaB in maintaining survival and function in hematopoietic stem and progenitor cells and suggest that proposed strategies involving inhibition of NF-kappaB activation as an adjunct to cancer chemotherapy should be approached with caution. " ], "offsets": [ [ 0, 1123 ] ] } ]

[ { "id": "PMID-10233882_T1", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 41, 45 ] ], "normalized": [] }, { "id": "PMID-10233882_T2", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 360, 364 ] ], "normalized": [] }, { "id": "PMID-10233882_T3", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 460, 464 ] ], "normalized": [] }, { "id": "PMID-10233882_T4", "type": "Protein", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 605, 632 ] ], "normalized": [] }, { "id": "PMID-10233882_T5", "type": "Protein", "text": [ "interleukin-3" ], "offsets": [ [ 634, 647 ] ], "normalized": [] }, { "id": "PMID-10233882_T6", "type": "Protein", "text": [ "granulocyte-macrophage colony-stimulating factor" ], "offsets": [ [ 653, 701 ] ], "normalized": [] }, { "id": "PMID-10233882_T7", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 772, 776 ] ], "normalized": [] } ]

[ { "id": "PMID-10233882_E1", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 486, 493 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233882_T4" } ] }, { "id": "PMID-10233882_E2", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 486, 493 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233882_T5" } ] }, { "id": "PMID-10233882_E3", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 486, 493 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233882_T6" } ] } ]

[]

[]

[ { "id": "PMID-10233888__text", "type": "abstract", "text": [ "Unicellular-unilineage erythropoietic cultures: molecular analysis of regulatory gene expression at sibling cell level. \nIn vitro studies on hematopoietic control mechanisms have been hampered by the heterogeneity of the analyzed cell populations, ie, lack of lineage specificity and developmental stage homogeneity of progenitor/precursor cells growing in culture. We developed unicellular culture systems for unilineage differentiation of purified hematopoietic progenitor cells followed by daughter cell analysis at cellular and molecular level. In the culture system reported here, (1) the growth factor (GF) stimulus induces cord blood (CB) progenitor cells to proliferate and differentiate/mature exclusively along the erythroid lineage; (2) this erythropoietic wave is characterized by less than 4% apoptotic cells; (3) asymmetric divisions are virtually absent, ie, nonresponsive hematopoietic progenitors with no erythropoietic potential are forced into apoptosis; (4) the system is cell division controlled (cdc), ie, the number of divisions performed by each cell is monitored. Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was applied to this culture system to investigate gene expression of diverse receptors, markers of differentiation, and transcription factors (EKLF, GATA-1, GATA-2, p45 NF-E2, PU.1, and SCL/Tal1) at discrete stages of erythropoietic development. Freshly isolated CD34(+) cells expressed CD34, c-kit, PU.1, and GATA-2 but did not express CD36, erythropoietin receptor (EpoR), SCL/Tal1, EKLF, NF-E2, GATA-1, or glyocophorin A (GPA). In early to intermediate stages of erythroid differentiation we monitored the induction of CD36, Tal1, EKLF, NF-E2, and GATA-1 that preceeded expression of EpoR. In late stages of erythroid maturation, GPA was upregulated, whereas CD34, c-kit, PU.1, and GATA-2 were barely or not detected. In addition, competitive single-cell RT-PCR was used to assay CD34 mRNA transcripts in sibling CD34(+) CD38(-) cells differentiating in unilineage erythroid cultures: this analysis allowed us to semiquantitate the gradual downmodulation of CD34 mRNA from progenitor cells through their differentiating erythroid progeny. It is concluded that this novel culture system, coupled with single-cell RT-PCR analysis, may eliminate the ambiguities intrinsic to molecular studies on heterogeneous populations of hematopoietic progenitors/precursors growing in culture, particularly in the initial stages of development. " ], "offsets": [ [ 0, 2500 ] ] } ]

[ { "id": "PMID-10233888_T1", "type": "Protein", "text": [ "EKLF" ], "offsets": [ [ 1310, 1314 ] ], "normalized": [] }, { "id": "PMID-10233888_T2", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 1316, 1322 ] ], "normalized": [] }, { "id": "PMID-10233888_T3", "type": "Protein", "text": [ "GATA-2" ], "offsets": [ [ 1324, 1330 ] ], "normalized": [] }, { "id": "PMID-10233888_T4", "type": "Protein", "text": [ "p45 NF-E2" ], "offsets": [ [ 1332, 1341 ] ], "normalized": [] }, { "id": "PMID-10233888_T5", "type": "Protein", "text": [ "PU.1" ], "offsets": [ [ 1343, 1347 ] ], "normalized": [] }, { "id": "PMID-10233888_T6", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 1353, 1356 ] ], "normalized": [] }, { "id": "PMID-10233888_T7", "type": "Protein", "text": [ "Tal1" ], "offsets": [ [ 1357, 1361 ] ], "normalized": [] }, { "id": "PMID-10233888_T8", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 1430, 1434 ] ], "normalized": [] }, { "id": "PMID-10233888_T9", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 1454, 1458 ] ], "normalized": [] }, { "id": "PMID-10233888_T10", "type": "Protein", "text": [ "c-kit" ], "offsets": [ [ 1460, 1465 ] ], "normalized": [] }, { "id": "PMID-10233888_T11", "type": "Protein", "text": [ "PU.1" ], "offsets": [ [ 1467, 1471 ] ], "normalized": [] }, { "id": "PMID-10233888_T12", "type": "Protein", "text": [ "GATA-2" ], "offsets": [ [ 1477, 1483 ] ], "normalized": [] }, { "id": "PMID-10233888_T13", "type": "Protein", "text": [ "CD36" ], "offsets": [ [ 1504, 1508 ] ], "normalized": [] }, { "id": "PMID-10233888_T14", "type": "Protein", "text": [ "erythropoietin receptor" ], "offsets": [ [ 1510, 1533 ] ], "normalized": [] }, { "id": "PMID-10233888_T15", "type": "Protein", "text": [ "EpoR" ], "offsets": [ [ 1535, 1539 ] ], "normalized": [] }, { "id": "PMID-10233888_T16", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 1542, 1545 ] ], "normalized": [] }, { "id": "PMID-10233888_T17", "type": "Protein", "text": [ "Tal1" ], "offsets": [ [ 1546, 1550 ] ], "normalized": [] }, { "id": "PMID-10233888_T18", "type": "Protein", "text": [ "EKLF" ], "offsets": [ [ 1552, 1556 ] ], "normalized": [] }, { "id": "PMID-10233888_T19", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 1565, 1571 ] ], "normalized": [] }, { "id": "PMID-10233888_T20", "type": "Protein", "text": [ "glyocophorin A" ], "offsets": [ [ 1576, 1590 ] ], "normalized": [] }, { "id": "PMID-10233888_T21", "type": "Protein", "text": [ "GPA" ], "offsets": [ [ 1592, 1595 ] ], "normalized": [] }, { "id": "PMID-10233888_T22", "type": "Protein", "text": [ "CD36" ], "offsets": [ [ 1689, 1693 ] ], "normalized": [] }, { "id": "PMID-10233888_T23", "type": "Protein", "text": [ "Tal1" ], "offsets": [ [ 1695, 1699 ] ], "normalized": [] }, { "id": "PMID-10233888_T24", "type": "Protein", "text": [ "EKLF" ], "offsets": [ [ 1701, 1705 ] ], "normalized": [] }, { "id": "PMID-10233888_T25", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 1718, 1724 ] ], "normalized": [] }, { "id": "PMID-10233888_T26", "type": "Protein", "text": [ "EpoR" ], "offsets": [ [ 1754, 1758 ] ], "normalized": [] }, { "id": "PMID-10233888_T27", "type": "Protein", "text": [ "GPA" ], "offsets": [ [ 1800, 1803 ] ], "normalized": [] }, { "id": "PMID-10233888_T28", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 1829, 1833 ] ], "normalized": [] }, { "id": "PMID-10233888_T29", "type": "Protein", "text": [ "c-kit" ], "offsets": [ [ 1835, 1840 ] ], "normalized": [] }, { "id": "PMID-10233888_T30", "type": "Protein", "text": [ "PU.1" ], "offsets": [ [ 1842, 1846 ] ], "normalized": [] }, { "id": "PMID-10233888_T31", "type": "Protein", "text": [ "GATA-2" ], "offsets": [ [ 1852, 1858 ] ], "normalized": [] }, { "id": "PMID-10233888_T32", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 1950, 1954 ] ], "normalized": [] }, { "id": "PMID-10233888_T33", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 1983, 1987 ] ], "normalized": [] }, { "id": "PMID-10233888_T34", "type": "Protein", "text": [ "CD38" ], "offsets": [ [ 1991, 1995 ] ], "normalized": [] }, { "id": "PMID-10233888_T35", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 2128, 2132 ] ], "normalized": [] } ]

[ { "id": "PMID-10233888_E1", "type": "Gene_expression", "trigger": { "text": [ "gene expression" ], "offsets": [ [ 1217, 1232 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T1" } ] }, { "id": "PMID-10233888_E2", "type": "Gene_expression", "trigger": { "text": [ "gene expression" ], "offsets": [ [ 1217, 1232 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T4" } ] }, { "id": "PMID-10233888_E3", "type": "Gene_expression", "trigger": { "text": [ "gene expression" ], "offsets": [ [ 1217, 1232 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T5" } ] }, { "id": "PMID-10233888_E4", "type": "Gene_expression", "trigger": { "text": [ "gene expression" ], "offsets": [ [ 1217, 1232 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T3" } ] }, { "id": "PMID-10233888_E5", "type": "Gene_expression", "trigger": { "text": [ "gene expression" ], "offsets": [ [ 1217, 1232 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T6" } ] }, { "id": "PMID-10233888_E6", "type": "Gene_expression", "trigger": { "text": [ "gene expression" ], "offsets": [ [ 1217, 1232 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T2" } ] }, { "id": "PMID-10233888_E7", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1444, 1453 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T9" } ] }, { "id": "PMID-10233888_E8", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1444, 1453 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T11" } ] }, { "id": "PMID-10233888_E9", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1444, 1453 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T10" } ] }, { "id": "PMID-10233888_E10", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1444, 1453 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T12" } ] }, { "id": "PMID-10233888_E11", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 1496, 1503 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T16" } ] }, { "id": "PMID-10233888_E12", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 1496, 1503 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T15" } ] }, { "id": "PMID-10233888_E13", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 1496, 1503 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T19" } ] }, { "id": "PMID-10233888_E14", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 1496, 1503 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T18" } ] }, { "id": "PMID-10233888_E15", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 1496, 1503 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T13" } ] }, { "id": "PMID-10233888_E16", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 1496, 1503 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T21" } ] }, { "id": "PMID-10233888_E17", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1676, 1685 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T22" } ] }, { "id": "PMID-10233888_E18", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1676, 1685 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T24" } ] }, { "id": "PMID-10233888_E19", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1676, 1685 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T23" } ] }, { "id": "PMID-10233888_E20", "type": "Gene_expression", "trigger": { "text": [ "induction" ], "offsets": [ [ 1676, 1685 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T25" } ] }, { "id": "PMID-10233888_E21", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1740, 1750 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T26" } ] }, { "id": "PMID-10233888_E22", "type": "Positive_regulation", "trigger": { "text": [ "upregulated" ], "offsets": [ [ 1808, 1819 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T27" } ] }, { "id": "PMID-10233888_E23", "type": "Gene_expression", "trigger": { "text": [ "detected" ], "offsets": [ [ 1878, 1886 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T30" } ] }, { "id": "PMID-10233888_E24", "type": "Gene_expression", "trigger": { "text": [ "detected" ], "offsets": [ [ 1878, 1886 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T29" } ] }, { "id": "PMID-10233888_E25", "type": "Gene_expression", "trigger": { "text": [ "detected" ], "offsets": [ [ 1878, 1886 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T28" } ] }, { "id": "PMID-10233888_E26", "type": "Gene_expression", "trigger": { "text": [ "detected" ], "offsets": [ [ 1878, 1886 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T31" } ] }, { "id": "PMID-10233888_E27", "type": "Transcription", "trigger": { "text": [ "mRNA transcripts" ], "offsets": [ [ 1955, 1971 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T32" } ] }, { "id": "PMID-10233888_E28", "type": "Negative_regulation", "trigger": { "text": [ "downmodulation" ], "offsets": [ [ 2110, 2124 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233888_T35" } ] } ]

[ { "id": "PMID-10233888_1", "entity_ids": [ "PMID-10233888_T15", "PMID-10233888_T14" ] }, { "id": "PMID-10233888_2", "entity_ids": [ "PMID-10233888_T21", "PMID-10233888_T20" ] }, { "id": "PMID-10233888_3", "entity_ids": [ "PMID-10233888_T16", "PMID-10233888_T17" ] } ]

[]

[ { "id": "PMID-10233927__text", "type": "abstract", "text": [ "Control of cell cycle entry and apoptosis in B lymphocytes infected by Epstein-Barr virus. \nInfection of human B cells with Epstein-Barr virus (EBV) results in activation of the cell cycle and cell growth. To interpret the mechanisms by which EBV activates the cell, we have assayed many proteins involved in control of the G0 and G1 phases of the cell cycle and regulation of apoptosis. In EBV infection most of the changes, including the early induction of cyclin D2, are dependent on expression of EBV genes, but an alteration in the E2F-4 profile was partly independent of viral gene expression, presumably occurring in response to signal transduction activated when the virus binds to its receptor, CD21. By comparing the expression of genes controlling apoptosis, including those encoding several members of the BCL-2 family of proteins, the known relative resistance of EBV-immortalized B-cell lines to apoptosis induced by low serum was found to correlate with expression of both BCL-2 and A20. A20 can be regulated by the NF-kappaB transcription factor, which is known to be activated by the EBV LMP-1 protein. Quantitative assays demonstrated a direct temporal relationship between LMP-1 protein levels and active NF-kappaB during the time course of infection. " ], "offsets": [ [ 0, 1271 ] ] } ]

[ { "id": "PMID-10233927_T1", "type": "Protein", "text": [ "cyclin D2" ], "offsets": [ [ 459, 468 ] ], "normalized": [] }, { "id": "PMID-10233927_T2", "type": "Protein", "text": [ "E2F-4" ], "offsets": [ [ 537, 542 ] ], "normalized": [] }, { "id": "PMID-10233927_T3", "type": "Protein", "text": [ "CD21" ], "offsets": [ [ 704, 708 ] ], "normalized": [] }, { "id": "PMID-10233927_T4", "type": "Protein", "text": [ "BCL-2" ], "offsets": [ [ 988, 993 ] ], "normalized": [] }, { "id": "PMID-10233927_T5", "type": "Protein", "text": [ "A20" ], "offsets": [ [ 998, 1001 ] ], "normalized": [] }, { "id": "PMID-10233927_T6", "type": "Protein", "text": [ "A20" ], "offsets": [ [ 1003, 1006 ] ], "normalized": [] }, { "id": "PMID-10233927_T7", "type": "Protein", "text": [ "LMP-1" ], "offsets": [ [ 1105, 1110 ] ], "normalized": [] }, { "id": "PMID-10233927_T8", "type": "Protein", "text": [ "LMP-1" ], "offsets": [ [ 1192, 1197 ] ], "normalized": [] } ]

[ { "id": "PMID-10233927_E1", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 446, 455 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233927_T1" } ] }, { "id": "PMID-10233927_E2", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 474, 483 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233927_E1" } ] }, { "id": "PMID-10233927_E3", "type": "Regulation", "trigger": { "text": [ "alteration" ], "offsets": [ [ 519, 529 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233927_T2" } ] }, { "id": "PMID-10233927_E4", "type": "Regulation", "trigger": { "text": [ "independent" ], "offsets": [ [ 562, 573 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233927_E3" } ] }, { "id": "PMID-10233927_E5", "type": "Positive_regulation", "trigger": { "text": [ "occurring" ], "offsets": [ [ 611, 620 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233927_E3" } ] }, { "id": "PMID-10233927_E6", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 681, 686 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233927_T3" } ] }, { "id": "PMID-10233927_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 969, 979 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233927_T4" } ] }, { "id": "PMID-10233927_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 969, 979 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233927_T5" } ] }, { "id": "PMID-10233927_E9", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1014, 1023 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233927_T6" } ] } ]

[]

[]

[ { "id": "PMID-10233947__text", "type": "abstract", "text": [ "Immortalization of CD4(+) and CD8(+) T lymphocytes by human T-cell leukemia virus type 1 Tax mutants expressed in a functional molecular clone. \nThe human T-cell leukemia virus type 1 (HTLV-1) transcriptional trans-activator Tax has been demonstrated to have transforming activity in multiple cell culture and transgenic-mouse models. In addition to activating transcription from the viral long terminal repeat (LTR) through the cyclic AMP response element binding protein/activating transcription factor (CREB/ATF) family of transcription factors, Tax activates the expression of multiple cellular promoters through the NF-kappaB pathway of transcriptional activation. The Tax mutants M22 and M47 have previously been demonstrated to selectively abrogate the ability of Tax to activate transcription through the NF-kappaB or CREB/ATF pathway, respectively. These mutations were introduced in the tax gene of the ACH functional molecular clone of HTLV-1, and virus produced from the mutant ACH clones was examined for the ability to replicate and immortalize primary human lymphocytes. While virus derived from the clone containing the M47 mutation retained the ability to immortalize T lymphocytes, the M22 mutant lost the ability to immortalize infected cells. These results indicate that activation of the CREB/ATF pathway by Tax is dispensable for the immortalization of T cells by HTLV-1, whereas activation of the NF-kappaB pathway may be critical. " ], "offsets": [ [ 0, 1455 ] ] } ]

[ { "id": "PMID-10233947_T1", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 19, 22 ] ], "normalized": [] }, { "id": "PMID-10233947_T2", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 89, 92 ] ], "normalized": [] }, { "id": "PMID-10233947_T3", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 225, 228 ] ], "normalized": [] }, { "id": "PMID-10233947_T4", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 549, 552 ] ], "normalized": [] }, { "id": "PMID-10233947_T5", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 674, 677 ] ], "normalized": [] }, { "id": "PMID-10233947_T6", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 771, 774 ] ], "normalized": [] }, { "id": "PMID-10233947_T7", "type": "Protein", "text": [ "tax" ], "offsets": [ [ 897, 900 ] ], "normalized": [] }, { "id": "PMID-10233947_T8", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 1329, 1332 ] ], "normalized": [] } ]

[ { "id": "PMID-10233947_E1", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 101, 110 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10233947_T2" } ] } ]

[]

[]

[ { "id": "PMID-10235509__text", "type": "abstract", "text": [ "HIV-1 reactivation in resting peripheral blood mononuclear cells of infected adults upon in vitro CD4 cross-linking by ligands of the CDR2-loop in extracellular domain 1. \nHIV-1 infects resting peripheral blood mononuclear cells (PBMCs) but remains inactive state until subsequent cell activation. We have demonstrated that the cross-linking of cell surface CD4 by gp120-anti-gp120 immune complexes or heat-inactivated HIV-1 (iHIV-1) is sufficient to trigger activation signals leading to virus reactivation (9). In this study, we demonstrate that NF-kappaB nuclear translocation and stimulation of virus production by iHIV-1 were strictly linked to the concentrations of viral proteins used as exogenous stimuli. Moreover, we further investigated the physiologic relevance of these observations. When submitted to an in vitro CD4 cross-linking by iHIV-1, PBMCs from HIV-1-infected patients were found to produce virus. This viral reactivation was associated with increased NF-kappaB nuclear translocation in patients' PBMCs. Additionally, virus reactivation in resting PBMCs infected in vitro with HIV-1 was found to be specifically induced by ligands of the CDR2-loop in domain 1 (D1) of CD4 (virus envelope and anti-CD4 monoclonal antibodies). In contrast, virus reactivation was not observed following CD4 oligomerization by antibodies that bind other epitopes in D1, including the D1/CDR3-loop. Finally, soluble CD4 (sCD4) prevented virus reactivation by D1/CDR2-loop ligands. Our results indicate that the signaling events initiated in PBMCs by oligomerization of CD4 at the D1/CDR2-loop can trigger HIV-1 upregulation in infected individuals. " ], "offsets": [ [ 0, 1650 ] ] } ]

[ { "id": "PMID-10235509_T1", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 98, 101 ] ], "normalized": [] }, { "id": "PMID-10235509_T2", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 358, 361 ] ], "normalized": [] }, { "id": "PMID-10235509_T3", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 827, 830 ] ], "normalized": [] }, { "id": "PMID-10235509_T4", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1190, 1193 ] ], "normalized": [] }, { "id": "PMID-10235509_T5", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1219, 1222 ] ], "normalized": [] }, { "id": "PMID-10235509_T6", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1306, 1309 ] ], "normalized": [] }, { "id": "PMID-10235509_T7", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1417, 1420 ] ], "normalized": [] }, { "id": "PMID-10235509_T8", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1570, 1573 ] ], "normalized": [] } ]

[ { "id": "PMID-10235509_E1", "type": "Binding", "trigger": { "text": [ "cross-linking" ], "offsets": [ [ 102, 115 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10235509_T1" } ] }, { "id": "PMID-10235509_E2", "type": "Binding", "trigger": { "text": [ "cross-linking" ], "offsets": [ [ 328, 341 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10235509_T2" } ] }, { "id": "PMID-10235509_E3", "type": "Binding", "trigger": { "text": [ "cross-linking" ], "offsets": [ [ 831, 844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10235509_T3" } ] }, { "id": "PMID-10235509_E4", "type": "Binding", "trigger": { "text": [ "oligomerization" ], "offsets": [ [ 1310, 1325 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10235509_T6" } ] }, { "id": "PMID-10235509_E5", "type": "Binding", "trigger": { "text": [ "oligomerization" ], "offsets": [ [ 1551, 1566 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10235509_T8" } ] } ]

[]

[]

[ { "id": "PMID-10318942__text", "type": "abstract", "text": [ "Defining therapeutic targets by using adenovirus: blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. \nThe role of the transcription factor NF-kappaB in the pathogenesis of rheumatoid arthritis has long been a subject of controversy. We used an adenoviral technique of blocking NF-kappaB through overexpression of the inhibitory subunit IkappaBalpha, which has the advantage that it can be used in the diseased tissue itself, with >90% of the synovial macrophages, fibroblasts, and T cells infected. We found that the spontaneous production of tumor necrosis factor alpha and other pro-inflammatory cytokines is NF-kappaB-dependent in rheumatoid synovial tissue, in contrast to the main anti-inflammatory mediators, like IL-10 and -11, and the IL-1 receptor antagonist. Of even more interest, IkappaBalpha overexpression inhibited the production of matrix metalloproteinases 1 and 3 while not affecting their tissue inhibitor. Blocking NF-kappaB in the rheumatoid joint thus has a very beneficial profile, reducing both the inflammatory response and the tissue destruction. The adenoviral technique described here has widespread applicability, allowing rapid testing of the effects of blocking a potential therapeutic target in either cultures of normal cells or in the diseased tissue itself. " ], "offsets": [ [ 0, 1378 ] ] } ]

[ { "id": "PMID-10318942_T1", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 421, 433 ] ], "normalized": [] }, { "id": "PMID-10318942_T2", "type": "Protein", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 628, 655 ] ], "normalized": [] }, { "id": "PMID-10318942_T3", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 805, 810 ] ], "normalized": [] }, { "id": "PMID-10318942_T4", "type": "Protein", "text": [ "-11" ], "offsets": [ [ 815, 818 ] ], "normalized": [] }, { "id": "PMID-10318942_T5", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 877, 889 ] ], "normalized": [] }, { "id": "PMID-10318942_T6", "type": "Protein", "text": [ "matrix metalloproteinases 1" ], "offsets": [ [ 933, 960 ] ], "normalized": [] }, { "id": "PMID-10318942_T7", "type": "Protein", "text": [ "3" ], "offsets": [ [ 965, 966 ] ], "normalized": [] } ]

[ { "id": "PMID-10318942_E1", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 380, 394 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10318942_E2" } ] }, { "id": "PMID-10318942_E2", "type": "Negative_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 380, 394 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10318942_T1" } ] }, { "id": "PMID-10318942_E3", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 614, 624 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10318942_T2" } ] }, { "id": "PMID-10318942_E4", "type": "Regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 706, 715 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10318942_T3" } ] }, { "id": "PMID-10318942_E5", "type": "Regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 706, 715 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10318942_E3" } ] }, { "id": "PMID-10318942_E6", "type": "Regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 706, 715 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10318942_T4" } ] }, { "id": "PMID-10318942_E7", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 890, 904 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10318942_T5" } ] }, { "id": "PMID-10318942_E8", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 890, 904 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10318942_E7" } ] }, { "id": "PMID-10318942_E9", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 905, 914 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10318942_E12" }, { "role": "Cause", "ref_id": "PMID-10318942_E8" } ] }, { "id": "PMID-10318942_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 905, 914 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10318942_E11" }, { "role": "Cause", "ref_id": "PMID-10318942_E8" } ] }, { "id": "PMID-10318942_E11", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 919, 929 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10318942_T7" } ] }, { "id": "PMID-10318942_E12", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 919, 929 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10318942_T6" } ] }, { "id": "PMID-10318942_E13", "type": "Regulation", "trigger": { "text": [ "affecting" ], "offsets": [ [ 977, 986 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10318942_T6" }, { "role": "Cause", "ref_id": "PMID-10318942_E8" } ] }, { "id": "PMID-10318942_E14", "type": "Regulation", "trigger": { "text": [ "affecting" ], "offsets": [ [ 977, 986 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10318942_T7" }, { "role": "Cause", "ref_id": "PMID-10318942_E8" } ] } ]

[]

[]

[ { "id": "PMID-10327050__text", "type": "abstract", "text": [ "Cell growth-regulated expression of mammalian MCM5 and MCM6 genes mediated by the transcription factor E2F. \nInitiation of DNA replication requires the function of MCM gene products, which participate in ensuring that DNA replication occurs only once in the cell cycle. Expression of all mammalian genes of the MCM family is induced by growth stimulation, unlike yeast, and the mRNA levels peak at G1/S boundary. In this study, we examined the transcriptional activities of isolated human MCM gene promoters. Human MCM5 and MCM6 promoters with mutation in the E2F sites failed in promoter regulation following serum stimulation and exogenous E2F expression. In addition, we identified a novel E2F-like sequence in human MCM6 promoter which cooperates with the authentic E2F sites in E2F-dependent regulation. Forced expression of E2F1 could induce expression of all members of the endogenous MCM genes in rat embryonal fibroblast REF52 cells. Our results demonstrated that the growth-regulated expression of mammalian MCM5 and MCM6 genes, and presumably other MCM members, is primarily regulated by E2F through binding to multiple E2F sites in the promoters. " ], "offsets": [ [ 0, 1159 ] ] } ]

[ { "id": "PMID-10327050_T1", "type": "Protein", "text": [ "MCM5" ], "offsets": [ [ 46, 50 ] ], "normalized": [] }, { "id": "PMID-10327050_T2", "type": "Protein", "text": [ "MCM6" ], "offsets": [ [ 55, 59 ] ], "normalized": [] }, { "id": "PMID-10327050_T3", "type": "Protein", "text": [ "MCM5" ], "offsets": [ [ 515, 519 ] ], "normalized": [] }, { "id": "PMID-10327050_T4", "type": "Protein", "text": [ "MCM6" ], "offsets": [ [ 524, 528 ] ], "normalized": [] }, { "id": "PMID-10327050_T5", "type": "Protein", "text": [ "MCM6" ], "offsets": [ [ 720, 724 ] ], "normalized": [] }, { "id": "PMID-10327050_T6", "type": "Protein", "text": [ "E2F1" ], "offsets": [ [ 830, 834 ] ], "normalized": [] }, { "id": "PMID-10327050_T7", "type": "Protein", "text": [ "MCM5" ], "offsets": [ [ 1018, 1022 ] ], "normalized": [] }, { "id": "PMID-10327050_T8", "type": "Protein", "text": [ "MCM6" ], "offsets": [ [ 1027, 1031 ] ], "normalized": [] }, { "id": "PMID-10327050_T12", "type": "Entity", "text": [ "promoters" ], "offsets": [ [ 529, 538 ] ], "normalized": [] }, { "id": "PMID-10327050_T15", "type": "Entity", "text": [ "E2F-like sequence" ], "offsets": [ [ 693, 710 ] ], "normalized": [] } ]

[ { "id": "PMID-10327050_E1", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 12, 21 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_E4" } ] }, { "id": "PMID-10327050_E2", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 12, 21 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_E3" } ] }, { "id": "PMID-10327050_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 22, 32 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_T1" } ] }, { "id": "PMID-10327050_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 22, 32 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_T2" } ] }, { "id": "PMID-10327050_E5", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 66, 74 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_E4" } ] }, { "id": "PMID-10327050_E6", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 66, 74 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_E3" } ] }, { "id": "PMID-10327050_E7", "type": "Negative_regulation", "trigger": { "text": [ "failed" ], "offsets": [ [ 570, 576 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_E10" } ] }, { "id": "PMID-10327050_E8", "type": "Negative_regulation", "trigger": { "text": [ "failed" ], "offsets": [ [ 570, 576 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_E9" } ] }, { "id": "PMID-10327050_E9", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 589, 599 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_T3" }, { "role": "Site", "ref_id": "PMID-10327050_T12" } ] }, { "id": "PMID-10327050_E10", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 589, 599 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_T4" }, { "role": "Site", "ref_id": "PMID-10327050_T12" } ] }, { "id": "PMID-10327050_E11", "type": "Regulation", "trigger": { "text": [ "cooperates" ], "offsets": [ [ 740, 750 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_E10" }, { "role": "Cause", "ref_id": "PMID-10327050_T5" }, { "role": "CSite", "ref_id": "PMID-10327050_T15" } ] }, { "id": "PMID-10327050_E12", "type": "Regulation", "trigger": { "text": [ "cooperates" ], "offsets": [ [ 740, 750 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_E9" }, { "role": "Cause", "ref_id": "PMID-10327050_T5" }, { "role": "CSite", "ref_id": "PMID-10327050_T15" } ] }, { "id": "PMID-10327050_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 816, 826 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_T6" } ] }, { "id": "PMID-10327050_E14", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 984, 993 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_E17" } ] }, { "id": "PMID-10327050_E15", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 984, 993 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_E16" } ] }, { "id": "PMID-10327050_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 994, 1004 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_T7" } ] }, { "id": "PMID-10327050_E17", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 994, 1004 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_T8" } ] }, { "id": "PMID-10327050_E18", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1086, 1095 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_E17" }, { "role": "Cause", "ref_id": "PMID-10327050_E23" } ] }, { "id": "PMID-10327050_E19", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1086, 1095 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_E16" }, { "role": "Cause", "ref_id": "PMID-10327050_E22" } ] }, { "id": "PMID-10327050_E20", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1086, 1095 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_E16" }, { "role": "Cause", "ref_id": "PMID-10327050_E23" } ] }, { "id": "PMID-10327050_E21", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1086, 1095 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_E17" }, { "role": "Cause", "ref_id": "PMID-10327050_E22" } ] }, { "id": "PMID-10327050_E22", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1111, 1118 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_T8" } ] }, { "id": "PMID-10327050_E23", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1111, 1118 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10327050_T7" } ] } ]

[]

[]

[ { "id": "PMID-10328874__text", "type": "abstract", "text": [ "Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. \nRecent studies have shown that the non-steroidal anti-inflammatory drugs (NSAIDs) activate heat shock transcription factor (HSF1) from a latent cytoplasmic form to a nuclear, DNA binding state. As HSF1 can function as both an activator of heat shock genes and a repressor of non-heat shock genes such as IL1B and c- fos, we have examined the potential role of HSF1 in the effects of NSAIDs on gene expression in a human monocytic cell line THP-1. We found that two members of the NSAIDs, sodium salicylate and sulindac repress the IL1B promoter to similar degree to heat shock or HSF1 overexpression. In addition, sodium salicylate and additional NSAIDs used at concentrations that activate HSF1 also inhibited the expression of other monocytic genes (TNF-alpha, IL-1beta, IL-6, IL-8, IL-10, ICAM-1) activated by exposure to a pro-inflammatory stimulus (lipopolysaccharide, LPS). At least in the case of the IL1B promoter, repression did not seem to involve another factor whose activity is affected by the NSAIDs, NFkappaB as the IL1B promoter fragment used in our studies is not NFkappaB responsive and binds specifically to HSF1. Exposure to NSAIDs had a complex effect on HSP gene expression and while sulindac activated the stress responsive HSP70B promoter, sodium salicylate did not. In addition, only a subset of the NSAIDs induced HSP70 mRNA species. These findings reflect the properties of HSF1 which can be activated to at least two DNA binding forms only one of which activates heat shock promoters and suggest that individual NSAID family members may differentially induce one or other of these forms. Overall therefore, exposure to NSAIDs leads to a profound switch in gene expression in monocytic cells, with suppression of genes involved in macrophage activation and induction of stress genes and HSF1 appears to play a regulatory role in these effects. Copyright 1999 Academic Press. " ], "offsets": [ [ 0, 2014 ] ] } ]

[ { "id": "PMID-10328874_T1", "type": "Protein", "text": [ "HSF1" ], "offsets": [ [ 236, 240 ] ], "normalized": [] }, { "id": "PMID-10328874_T2", "type": "Protein", "text": [ "HSF1" ], "offsets": [ [ 309, 313 ] ], "normalized": [] }, { "id": "PMID-10328874_T3", "type": "Protein", "text": [ "IL1B" ], "offsets": [ [ 416, 420 ] ], "normalized": [] }, { "id": "PMID-10328874_T4", "type": "Protein", "text": [ "c- fos" ], "offsets": [ [ 425, 431 ] ], "normalized": [] }, { "id": "PMID-10328874_T5", "type": "Protein", "text": [ "HSF1" ], "offsets": [ [ 472, 476 ] ], "normalized": [] }, { "id": "PMID-10328874_T6", "type": "Protein", "text": [ "IL1B" ], "offsets": [ [ 643, 647 ] ], "normalized": [] }, { "id": "PMID-10328874_T7", "type": "Protein", "text": [ "HSF1" ], "offsets": [ [ 692, 696 ] ], "normalized": [] }, { "id": "PMID-10328874_T8", "type": "Protein", "text": [ "HSF1" ], "offsets": [ [ 803, 807 ] ], "normalized": [] }, { "id": "PMID-10328874_T9", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 864, 873 ] ], "normalized": [] }, { "id": "PMID-10328874_T10", "type": "Protein", "text": [ "IL-1beta" ], "offsets": [ [ 875, 883 ] ], "normalized": [] }, { "id": "PMID-10328874_T11", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 885, 889 ] ], "normalized": [] }, { "id": "PMID-10328874_T12", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 891, 895 ] ], "normalized": [] }, { "id": "PMID-10328874_T13", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 897, 902 ] ], "normalized": [] }, { "id": "PMID-10328874_T14", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 904, 910 ] ], "normalized": [] }, { "id": "PMID-10328874_T15", "type": "Protein", "text": [ "IL1B" ], "offsets": [ [ 1020, 1024 ] ], "normalized": [] }, { "id": "PMID-10328874_T16", "type": "Protein", "text": [ "IL1B" ], "offsets": [ [ 1143, 1147 ] ], "normalized": [] }, { "id": "PMID-10328874_T17", "type": "Protein", "text": [ "HSF1" ], "offsets": [ [ 1239, 1243 ] ], "normalized": [] }, { "id": "PMID-10328874_T18", "type": "Protein", "text": [ "HSP70B" ], "offsets": [ [ 1359, 1365 ] ], "normalized": [] }, { "id": "PMID-10328874_T19", "type": "Protein", "text": [ "HSP70" ], "offsets": [ [ 1452, 1457 ] ], "normalized": [] }, { "id": "PMID-10328874_T20", "type": "Protein", "text": [ "HSF1" ], "offsets": [ [ 1513, 1517 ] ], "normalized": [] }, { "id": "PMID-10328874_T21", "type": "Protein", "text": [ "HSF1" ], "offsets": [ [ 1926, 1930 ] ], "normalized": [] }, { "id": "PMID-10328874_T27", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 648, 656 ] ], "normalized": [] }, { "id": "PMID-10328874_T34", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1025, 1033 ] ], "normalized": [] }, { "id": "PMID-10328874_T36", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1148, 1156 ] ], "normalized": [] }, { "id": "PMID-10328874_T41", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1366, 1374 ] ], "normalized": [] } ]

[ { "id": "PMID-10328874_E1", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 194, 202 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E2" } ] }, { "id": "PMID-10328874_E2", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 291, 298 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T1" } ] }, { "id": "PMID-10328874_E3", "type": "Positive_regulation", "trigger": { "text": [ "activator" ], "offsets": [ [ 338, 347 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T3" }, { "role": "Cause", "ref_id": "PMID-10328874_T2" } ] }, { "id": "PMID-10328874_E4", "type": "Positive_regulation", "trigger": { "text": [ "activator" ], "offsets": [ [ 338, 347 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T4" }, { "role": "Cause", "ref_id": "PMID-10328874_T2" } ] }, { "id": "PMID-10328874_E5", "type": "Negative_regulation", "trigger": { "text": [ "repressor" ], "offsets": [ [ 374, 383 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T3" }, { "role": "Cause", "ref_id": "PMID-10328874_T2" } ] }, { "id": "PMID-10328874_E6", "type": "Negative_regulation", "trigger": { "text": [ "repressor" ], "offsets": [ [ 374, 383 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T4" }, { "role": "Cause", "ref_id": "PMID-10328874_T2" } ] }, { "id": "PMID-10328874_E7", "type": "Negative_regulation", "trigger": { "text": [ "repress" ], "offsets": [ [ 631, 638 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T6" }, { "role": "Site", "ref_id": "PMID-10328874_T27" } ] }, { "id": "PMID-10328874_E8", "type": "Negative_regulation", "trigger": { "text": [ "repress" ], "offsets": [ [ 631, 638 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E12" } ] }, { "id": "PMID-10328874_E9", "type": "Negative_regulation", "trigger": { "text": [ "repress" ], "offsets": [ [ 631, 638 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E11" } ] }, { "id": "PMID-10328874_E10", "type": "Negative_regulation", "trigger": { "text": [ "repress" ], "offsets": [ [ 631, 638 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E13" } ] }, { "id": "PMID-10328874_E11", "type": "Positive_regulation", "trigger": { "text": [ "over" ], "offsets": [ [ 697, 701 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E16" } ] }, { "id": "PMID-10328874_E12", "type": "Positive_regulation", "trigger": { "text": [ "over" ], "offsets": [ [ 697, 701 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E14" } ] }, { "id": "PMID-10328874_E13", "type": "Positive_regulation", "trigger": { "text": [ "over" ], "offsets": [ [ 697, 701 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E15" } ] }, { "id": "PMID-10328874_E14", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 701, 711 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T3" } ] }, { "id": "PMID-10328874_E15", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 701, 711 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T4" } ] }, { "id": "PMID-10328874_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 701, 711 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T7" } ] }, { "id": "PMID-10328874_E17", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 794, 802 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T8" } ] }, { "id": "PMID-10328874_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 813, 822 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E30" } ] }, { "id": "PMID-10328874_E19", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 813, 822 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E34" } ] }, { "id": "PMID-10328874_E20", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 813, 822 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E31" } ] }, { "id": "PMID-10328874_E21", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 813, 822 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E32" } ] }, { "id": "PMID-10328874_E22", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 813, 822 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E33" } ] }, { "id": "PMID-10328874_E23", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 813, 822 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E35" } ] }, { "id": "PMID-10328874_E24", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 827, 837 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T12" } ] }, { "id": "PMID-10328874_E25", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 827, 837 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T11" } ] }, { "id": "PMID-10328874_E26", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 827, 837 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T14" } ] }, { "id": "PMID-10328874_E27", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 827, 837 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T13" } ] }, { "id": "PMID-10328874_E28", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 827, 837 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T9" } ] }, { "id": "PMID-10328874_E29", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 827, 837 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T10" } ] }, { "id": "PMID-10328874_E30", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 912, 921 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E29" } ] }, { "id": "PMID-10328874_E31", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 912, 921 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E24" } ] }, { "id": "PMID-10328874_E32", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 912, 921 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E25" } ] }, { "id": "PMID-10328874_E33", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 912, 921 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E26" } ] }, { "id": "PMID-10328874_E34", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 912, 921 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E27" } ] }, { "id": "PMID-10328874_E35", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 912, 921 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E28" } ] }, { "id": "PMID-10328874_E36", "type": "Negative_regulation", "trigger": { "text": [ "repression" ], "offsets": [ [ 1035, 1045 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T15" }, { "role": "Site", "ref_id": "PMID-10328874_T34" } ] }, { "id": "PMID-10328874_E37", "type": "Regulation", "trigger": { "text": [ "responsive" ], "offsets": [ [ 1202, 1212 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T16" }, { "role": "Site", "ref_id": "PMID-10328874_T36" } ] }, { "id": "PMID-10328874_E38", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 1217, 1222 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T16" }, { "role": "Theme", "ref_id": "PMID-10328874_T17" }, { "role": "Site", "ref_id": "PMID-10328874_T36" } ] }, { "id": "PMID-10328874_E39", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1327, 1336 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T18" }, { "role": "Site", "ref_id": "PMID-10328874_T41" } ] }, { "id": "PMID-10328874_E40", "type": "Positive_regulation", "trigger": { "text": [ "responsive" ], "offsets": [ [ 1348, 1358 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T18" }, { "role": "Site", "ref_id": "PMID-10328874_T41" } ] }, { "id": "PMID-10328874_E41", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1444, 1451 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T19" } ] }, { "id": "PMID-10328874_E42", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1531, 1540 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_E43" } ] }, { "id": "PMID-10328874_E43", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1561, 1568 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10328874_T20" } ] } ]

[]

[]

[ { "id": "PMID-10329625__text", "type": "abstract", "text": [ "Disruption of alpha beta but not of gamma delta T cell development by overexpression of the helix-loop-helix protein Id3 in committed T cell progenitors. \nEnforced expression of Id3, which has the capacity to inhibit many basic helix-loop-helix (bHLH) transcription factors, in human CD34(+) hematopoietic progenitor cells that have not undergone T cell receptor (TCR) gene rearrangements inhibits development of the transduced cells into TCRalpha beta and gamma delta cells in a fetal thymic organ culture (FTOC). Here we document that overexpression of Id3, in progenitors that have initiated TCR gene rearrangements (pre-T cells), inhibits development into TCRalpha beta but not into TCRgamma delta T cells. Furthermore, Id3 impedes expression of recombination activating genes and downregulates pre-Talpha mRNA. These observations suggest possible mechanisms by which Id3 overexpression can differentially affect development of pre-T cells into TCRalpha beta and gamma delta cells. We also observed that cell surface CD4(-)CD8(-)CD3(-) cells with rearranged TCR genes developed from Id3-transduced but not from control-transduced pre-T cells in an FTOC. These cells had properties of both natural killer (NK) and pre-T cells. These findings suggest that bHLH factors are required to control T cell development after the T/NK developmental checkpoint. " ], "offsets": [ [ 0, 1355 ] ] } ]

[ { "id": "PMID-10329625_T1", "type": "Protein", "text": [ "Id3" ], "offsets": [ [ 117, 120 ] ], "normalized": [] }, { "id": "PMID-10329625_T2", "type": "Protein", "text": [ "Id3" ], "offsets": [ [ 178, 181 ] ], "normalized": [] }, { "id": "PMID-10329625_T3", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 284, 288 ] ], "normalized": [] }, { "id": "PMID-10329625_T4", "type": "Protein", "text": [ "Id3" ], "offsets": [ [ 555, 558 ] ], "normalized": [] }, { "id": "PMID-10329625_T5", "type": "Protein", "text": [ "Id3" ], "offsets": [ [ 724, 727 ] ], "normalized": [] }, { "id": "PMID-10329625_T6", "type": "Protein", "text": [ "Id3" ], "offsets": [ [ 872, 875 ] ], "normalized": [] }, { "id": "PMID-10329625_T7", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1021, 1024 ] ], "normalized": [] }, { "id": "PMID-10329625_T8", "type": "Protein", "text": [ "Id3" ], "offsets": [ [ 1087, 1090 ] ], "normalized": [] } ]

[ { "id": "PMID-10329625_E1", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 70, 84 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329625_E2" } ] }, { "id": "PMID-10329625_E2", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 70, 84 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329625_T1" } ] }, { "id": "PMID-10329625_E3", "type": "Positive_regulation", "trigger": { "text": [ "Enforced" ], "offsets": [ [ 155, 163 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329625_E4" } ] }, { "id": "PMID-10329625_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 164, 174 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329625_T2" } ] }, { "id": "PMID-10329625_E5", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 537, 551 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329625_T4" } ] }, { "id": "PMID-10329625_E6", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 876, 890 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329625_T6" } ] }, { "id": "PMID-10329625_E7", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 876, 890 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329625_E6" } ] } ]

[]

[]

[ { "id": "PMID-10329626__text", "type": "abstract", "text": [ "Rel/NF-kappaB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors. \nJagged1 belongs to the DSL family of ligands for Notch receptors that control the proliferation and differentiation of various cell lineages. However, little is known about the transcription factors that regulate its expression. Here, we show that Jagged1 is a Rel/NF-kappaB-responsive gene. Both c-Rel and RelA induced jagged1 gene expression, whereas a mutant defective for transactivation did not. Importantly, jagged1 transcripts were also upregulated by endogenous NF-kappaB activation and this effect was inhibited by a dominant mutant of IkappaBalpha, a physiological inhibitor of NF-kappaB. Cell surface expression of Jagged1 in c-Rel-expressing cell monolayers led to a functional interaction with lymphocytes expressing the Notch1/TAN-1 receptor. This correlated with the initiation of signaling downstream of Notch, as evidenced by increased levels of HES-1 transcripts in co-cultivated T cells and of CD23 transcripts in co-cultivated B cells. Consistent with its Rel/NF-kappaB-dependent induction, Jagged1 was found to be highly expressed in splenic B cells where c-Rel is expressed constitutively. These results demonstrate that c-Rel can trigger the Notch signaling pathway in neighboring cells by inducing jagged1 gene expression, and suggest a role for Jagged1 in B-cell activation, differentiation or function. These findings also highlight the potential for an interplay between the Notch and NF-kappaB signaling pathways in the immune system. " ], "offsets": [ [ 0, 1587 ] ] } ]

[ { "id": "PMID-10329626_T1", "type": "Protein", "text": [ "Jagged1" ], "offsets": [ [ 84, 91 ] ], "normalized": [] }, { "id": "PMID-10329626_T2", "type": "Protein", "text": [ "Jagged1" ], "offsets": [ [ 124, 131 ] ], "normalized": [] }, { "id": "PMID-10329626_T3", "type": "Protein", "text": [ "Jagged1" ], "offsets": [ [ 372, 379 ] ], "normalized": [] }, { "id": "PMID-10329626_T4", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 421, 426 ] ], "normalized": [] }, { "id": "PMID-10329626_T5", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 431, 435 ] ], "normalized": [] }, { "id": "PMID-10329626_T6", "type": "Protein", "text": [ "jagged1" ], "offsets": [ [ 444, 451 ] ], "normalized": [] }, { "id": "PMID-10329626_T7", "type": "Protein", "text": [ "jagged1" ], "offsets": [ [ 538, 545 ] ], "normalized": [] }, { "id": "PMID-10329626_T8", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 669, 681 ] ], "normalized": [] }, { "id": "PMID-10329626_T9", "type": "Protein", "text": [ "Jagged1" ], "offsets": [ [ 750, 757 ] ], "normalized": [] }, { "id": "PMID-10329626_T10", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 761, 766 ] ], "normalized": [] }, { "id": "PMID-10329626_T11", "type": "Protein", "text": [ "Notch1" ], "offsets": [ [ 858, 864 ] ], "normalized": [] }, { "id": "PMID-10329626_T12", "type": "Protein", "text": [ "TAN-1" ], "offsets": [ [ 865, 870 ] ], "normalized": [] }, { "id": "PMID-10329626_T13", "type": "Protein", "text": [ "HES-1" ], "offsets": [ [ 987, 992 ] ], "normalized": [] }, { "id": "PMID-10329626_T14", "type": "Protein", "text": [ "CD23" ], "offsets": [ [ 1037, 1041 ] ], "normalized": [] }, { "id": "PMID-10329626_T15", "type": "Protein", "text": [ "Jagged1" ], "offsets": [ [ 1135, 1142 ] ], "normalized": [] }, { "id": "PMID-10329626_T16", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 1201, 1206 ] ], "normalized": [] }, { "id": "PMID-10329626_T17", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 1267, 1272 ] ], "normalized": [] }, { "id": "PMID-10329626_T18", "type": "Protein", "text": [ "jagged1" ], "offsets": [ [ 1346, 1353 ] ], "normalized": [] }, { "id": "PMID-10329626_T19", "type": "Protein", "text": [ "Jagged1" ], "offsets": [ [ 1394, 1401 ] ], "normalized": [] } ]

[ { "id": "PMID-10329626_E1", "type": "Positive_regulation", "trigger": { "text": [ "inducing" ], "offsets": [ [ 57, 65 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_E2" } ] }, { "id": "PMID-10329626_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 70, 80 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_T1" } ] }, { "id": "PMID-10329626_E3", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 328, 336 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_E4" } ] }, { "id": "PMID-10329626_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 341, 351 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_T2" } ] }, { "id": "PMID-10329626_E5", "type": "Regulation", "trigger": { "text": [ "responsive" ], "offsets": [ [ 399, 409 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_T3" } ] }, { "id": "PMID-10329626_E6", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 436, 443 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_E9" }, { "role": "Cause", "ref_id": "PMID-10329626_T5" } ] }, { "id": "PMID-10329626_E7", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 436, 443 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_E9" }, { "role": "Cause", "ref_id": "PMID-10329626_T4" } ] }, { "id": "PMID-10329626_E8", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 436, 443 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_E9" } ] }, { "id": "PMID-10329626_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 457, 467 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_T6" } ] }, { "id": "PMID-10329626_E10", "type": "Positive_regulation", "trigger": { "text": [ "upregulated" ], "offsets": [ [ 568, 579 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_T7" } ] }, { "id": "PMID-10329626_E11", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 635, 644 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_E10" }, { "role": "Cause", "ref_id": "PMID-10329626_T8" } ] }, { "id": "PMID-10329626_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 736, 746 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_T9" } ] }, { "id": "PMID-10329626_E13", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 767, 777 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_T10" } ] }, { "id": "PMID-10329626_E14", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 843, 853 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_T11" } ] }, { "id": "PMID-10329626_E15", "type": "Positive_regulation", "trigger": { "text": [ "increased levels" ], "offsets": [ [ 967, 983 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_T13" } ] }, { "id": "PMID-10329626_E16", "type": "Positive_regulation", "trigger": { "text": [ "increased levels" ], "offsets": [ [ 967, 983 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_T14" } ] }, { "id": "PMID-10329626_E17", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1124, 1133 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_T15" } ] }, { "id": "PMID-10329626_E18", "type": "Positive_regulation", "trigger": { "text": [ "highly" ], "offsets": [ [ 1159, 1165 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_E19" } ] }, { "id": "PMID-10329626_E19", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1166, 1175 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_T15" } ] }, { "id": "PMID-10329626_E20", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1210, 1219 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_T16" } ] }, { "id": "PMID-10329626_E21", "type": "Positive_regulation", "trigger": { "text": [ "inducing" ], "offsets": [ [ 1337, 1345 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_E22" }, { "role": "Cause", "ref_id": "PMID-10329626_T17" } ] }, { "id": "PMID-10329626_E22", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1359, 1369 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329626_T18" } ] } ]

[ { "id": "PMID-10329626_1", "entity_ids": [ "PMID-10329626_T11", "PMID-10329626_T12" ] } ]

[]

[ { "id": "PMID-10329845__text", "type": "abstract", "text": [ "Transcriptional control of the IL-5 gene by human helper T cells: IL-5 synthesis is regulated independently from IL-2 or IL-4 synthesis. \nBACKGROUND: IL-5 is fundamentally involved in eosinophilic inflammation. Control of IL-5 production may be effective for the management of allergic diseases. OBJECTIVE: We aimed to find the transcriptional mechanisms that regulate the IL-5 gene to selectively control IL-5 synthesis. METHODS: Allergen-specific T-cell clones and T-cell hybridomas were established from the peripheral blood lymphocytes of patients with asthma, and the transcriptional regulation of the IL-5 gene was investigated with transient transfection and electrophoretic mobility shift analysis. RESULTS: A human IL-5 promoter/enhancer-luciferase gene construct, pIL-5(-511)Luc, was transcribed on activation of IL-5-producing T-cell clones, but not IL-5-nonproducing clones. pIL-5(-511)Luc was transcribed by T-cell hybridomas derived from fusion between IL-5-producing T-cell clones and an IL-5 gene-nonexpressing T-cell line, but not by hybridomas derived from IL-5-nonproducing T-cell clones. IL-5 synthesis was not only induced by T-cell receptor stimulation but also by IL-2 receptor stimulation. Binding of NF-AT, NF-kappaB, and AP-1 was induced by T-cell receptor (TcR) stimulation, although there was no significant upregulation of binding by IL-2 stimulation. CONCLUSION: IL-5 synthesis by human helper T cells is regulated at the transcriptional level. A unique transcriptional mechanism distinct from those regulating the IL-2 or IL-4 genes seems to control the IL-5 gene. Selective regulation of IL-5 gene transcription may be useful for treating eosinophlic inflammation. " ], "offsets": [ [ 0, 1697 ] ] } ]

[ { "id": "PMID-10329845_T1", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 31, 35 ] ], "normalized": [] }, { "id": "PMID-10329845_T2", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 66, 70 ] ], "normalized": [] }, { "id": "PMID-10329845_T3", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 113, 117 ] ], "normalized": [] }, { "id": "PMID-10329845_T4", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 121, 125 ] ], "normalized": [] }, { "id": "PMID-10329845_T5", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 150, 154 ] ], "normalized": [] }, { "id": "PMID-10329845_T6", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 222, 226 ] ], "normalized": [] }, { "id": "PMID-10329845_T7", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 373, 377 ] ], "normalized": [] }, { "id": "PMID-10329845_T8", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 406, 410 ] ], "normalized": [] }, { "id": "PMID-10329845_T9", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 607, 611 ] ], "normalized": [] }, { "id": "PMID-10329845_T10", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 724, 728 ] ], "normalized": [] }, { "id": "PMID-10329845_T11", "type": "Protein", "text": [ "luciferase" ], "offsets": [ [ 747, 757 ] ], "normalized": [] }, { "id": "PMID-10329845_T12", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 823, 827 ] ], "normalized": [] }, { "id": "PMID-10329845_T13", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 861, 865 ] ], "normalized": [] }, { "id": "PMID-10329845_T14", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 967, 971 ] ], "normalized": [] }, { "id": "PMID-10329845_T15", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 1003, 1007 ] ], "normalized": [] }, { "id": "PMID-10329845_T16", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 1075, 1079 ] ], "normalized": [] }, { "id": "PMID-10329845_T17", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 1108, 1112 ] ], "normalized": [] }, { "id": "PMID-10329845_T18", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1187, 1191 ] ], "normalized": [] }, { "id": "PMID-10329845_T19", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1363, 1367 ] ], "normalized": [] }, { "id": "PMID-10329845_T20", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 1393, 1397 ] ], "normalized": [] }, { "id": "PMID-10329845_T21", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1545, 1549 ] ], "normalized": [] }, { "id": "PMID-10329845_T22", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1553, 1557 ] ], "normalized": [] }, { "id": "PMID-10329845_T23", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 1585, 1589 ] ], "normalized": [] }, { "id": "PMID-10329845_T24", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 1620, 1624 ] ], "normalized": [] } ]

[ { "id": "PMID-10329845_E1", "type": "Regulation", "trigger": { "text": [ "Transcriptional control" ], "offsets": [ [ 0, 23 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T1" } ] }, { "id": "PMID-10329845_E2", "type": "Gene_expression", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 71, 80 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T2" } ] }, { "id": "PMID-10329845_E3", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 84, 93 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_E2" } ] }, { "id": "PMID-10329845_E4", "type": "Gene_expression", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 126, 135 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T3" } ] }, { "id": "PMID-10329845_E5", "type": "Gene_expression", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 126, 135 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T4" } ] }, { "id": "PMID-10329845_E6", "type": "Regulation", "trigger": { "text": [ "Control" ], "offsets": [ [ 211, 218 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_E7" } ] }, { "id": "PMID-10329845_E7", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 227, 237 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T6" } ] }, { "id": "PMID-10329845_E8", "type": "Transcription", "trigger": { "text": [ "transcriptional" ], "offsets": [ [ 328, 343 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T7" } ] }, { "id": "PMID-10329845_E9", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 360, 368 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_E8" } ] }, { "id": "PMID-10329845_E10", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 398, 405 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_E11" }, { "role": "Cause", "ref_id": "PMID-10329845_E9" } ] }, { "id": "PMID-10329845_E11", "type": "Gene_expression", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 411, 420 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T8" } ] }, { "id": "PMID-10329845_E12", "type": "Transcription", "trigger": { "text": [ "transcriptional regulation" ], "offsets": [ [ 573, 599 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T9" } ] }, { "id": "PMID-10329845_E13", "type": "Gene_expression", "trigger": { "text": [ "producing" ], "offsets": [ [ 828, 837 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T12" } ] }, { "id": "PMID-10329845_E14", "type": "Gene_expression", "trigger": { "text": [ "nonproducing" ], "offsets": [ [ 866, 878 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T13" } ] }, { "id": "PMID-10329845_E15", "type": "Gene_expression", "trigger": { "text": [ "producing" ], "offsets": [ [ 972, 981 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T14" } ] }, { "id": "PMID-10329845_E16", "type": "Gene_expression", "trigger": { "text": [ "nonexpressing" ], "offsets": [ [ 1013, 1026 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T15" } ] }, { "id": "PMID-10329845_E17", "type": "Gene_expression", "trigger": { "text": [ "nonproducing" ], "offsets": [ [ 1080, 1092 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T16" } ] }, { "id": "PMID-10329845_E18", "type": "Gene_expression", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 1113, 1122 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T17" } ] }, { "id": "PMID-10329845_E19", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1136, 1143 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_E18" } ] }, { "id": "PMID-10329845_E20", "type": "Gene_expression", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 1398, 1407 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T20" } ] }, { "id": "PMID-10329845_E21", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1435, 1444 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_E20" } ] }, { "id": "PMID-10329845_E22", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 1530, 1540 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T22" } ] }, { "id": "PMID-10329845_E23", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 1530, 1540 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T21" } ] }, { "id": "PMID-10329845_E24", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 1573, 1580 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T1" } ] }, { "id": "PMID-10329845_E25", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1606, 1616 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_E26" } ] }, { "id": "PMID-10329845_E26", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1630, 1643 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329845_T1" } ] } ]

[]

[]

[ { "id": "PMID-10329958__text", "type": "abstract", "text": [ "Regulation of low shear flow-induced HAEC VCAM-1 expression and monocyte adhesion. \nWe recently reported that prolonged exposure of human aortic endothelial cells (HAEC) to low shear stress flow patterns is associated with a sustained increase in the activated form of the transcriptional regulator nuclear factor-kappaB (NF-kappaB). Here we investigate the hypothesis that low shear-induced activation of NF-kappaB is responsible for enhanced expression of vascular cell adhesion molecule (VCAM-1) resulting in augmented endothelial cell-monocyte (EC-Mn) adhesion and that this activation is dependent on intracellular oxidant activity. Before exposure to low shear (2 dyn/cm2) for 6 h, HAEC were preincubated with or without the antioxidants pyrrolidine dithiocarbamate (PDTC) or N-acetyl-L-cysteine (NAC). PDTC strongly inhibited low shear-induced activation of NF-kappaB, expression of VCAM-1, and EC-Mn adhesion. Paradoxically, NAC exerted a positive effect on low shear-induced VCAM-1 expression and EC-Mn adhesion and only slightly downregulated NF-kappaB activation. However, cytokine-induced NF-kappaB activation and VCAM-1 expression are blocked by both PDTC and NAC. These data suggest that NF-kappaB plays a key role in low shear-induced VCAM-1 expression and that pathways mediating low shear- and cytokine-induced EC-Mn adhesion may be differentially regulated. " ], "offsets": [ [ 0, 1376 ] ] } ]

[ { "id": "PMID-10329958_T1", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 42, 48 ] ], "normalized": [] }, { "id": "PMID-10329958_T2", "type": "Protein", "text": [ "vascular cell adhesion molecule" ], "offsets": [ [ 458, 489 ] ], "normalized": [] }, { "id": "PMID-10329958_T3", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 491, 497 ] ], "normalized": [] }, { "id": "PMID-10329958_T4", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 890, 896 ] ], "normalized": [] }, { "id": "PMID-10329958_T5", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 984, 990 ] ], "normalized": [] }, { "id": "PMID-10329958_T6", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1126, 1132 ] ], "normalized": [] }, { "id": "PMID-10329958_T7", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1250, 1256 ] ], "normalized": [] } ]

[ { "id": "PMID-10329958_E1", "type": "Regulation", "trigger": { "text": [ "Regulation" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_E2" } ] }, { "id": "PMID-10329958_E2", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 29, 36 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_E3" } ] }, { "id": "PMID-10329958_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 49, 59 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_T1" } ] }, { "id": "PMID-10329958_E4", "type": "Positive_regulation", "trigger": { "text": [ "responsible for enhanced" ], "offsets": [ [ 419, 443 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_E5" } ] }, { "id": "PMID-10329958_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 444, 454 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_T3" } ] }, { "id": "PMID-10329958_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 823, 832 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_E7" } ] }, { "id": "PMID-10329958_E7", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 843, 850 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_E8" } ] }, { "id": "PMID-10329958_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 876, 886 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_T4" } ] }, { "id": "PMID-10329958_E9", "type": "Positive_regulation", "trigger": { "text": [ "exerted a positive effect" ], "offsets": [ [ 937, 962 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_E10" } ] }, { "id": "PMID-10329958_E10", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 976, 983 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_E11" } ] }, { "id": "PMID-10329958_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 991, 1001 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_T5" } ] }, { "id": "PMID-10329958_E12", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1093, 1100 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_E13" } ] }, { "id": "PMID-10329958_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1133, 1143 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_T6" } ] }, { "id": "PMID-10329958_E14", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1148, 1155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_E12" } ] }, { "id": "PMID-10329958_E15", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1242, 1249 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_E16" } ] }, { "id": "PMID-10329958_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1257, 1267 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10329958_T7" } ] } ]

[ { "id": "PMID-10329958_1", "entity_ids": [ "PMID-10329958_T3", "PMID-10329958_T2" ] } ]

[]

[ { "id": "PMID-10330189__text", "type": "abstract", "text": [ "Nuclear localization and formation of beta-catenin-lymphoid enhancer factor 1 complexes are not sufficient for activation of gene expression. \nIn response to activation of the Wnt signaling pathway, beta-catenin accumulates in the nucleus, where it cooperates with LEF/TCF (for lymphoid enhancer factor and T-cell factor) transcription factors to activate gene expression. The mechanisms by which beta-catenin undergoes this shift in location and participates in activation of gene transcription are unknown. We demonstrate here that beta-catenin can be imported into the nucleus independently of LEF/TCF binding, and it may also be exported from nuclei. We have introduced a small deletion within beta-catenin (Delta19) that disrupts binding to LEF-1, E-cadherin, and APC but not axin. This Delta19 beta-catenin mutant localizes to the nucleus because it may not be efficiently sequestered in the cytoplasm. The nuclear localization of Delta19 definitively demonstrates that the mechanisms by which beta-catenin localizes in the nucleus are completely independent of LEF/TCF factors. beta-Catenin and LEF-1 complexes can activate reporter gene expression in a transformed T-lymphocyte cell line (Jurkat) but not in normal T lymphocytes, even though both factors are nuclear. Thus, localization of both factors to the nucleus is not sufficient for activation of gene expression. Excess beta-catenin can squelch reporter gene activation by LEF-1-beta-catenin complexes but not activation by the transcription factor VP16. Taken together, these data suggest that a third component is necessary for gene activation and that this third component may vary with cell type. " ], "offsets": [ [ 0, 1667 ] ] } ]

[ { "id": "PMID-10330189_T1", "type": "Protein", "text": [ "beta-catenin" ], "offsets": [ [ 38, 50 ] ], "normalized": [] }, { "id": "PMID-10330189_T2", "type": "Protein", "text": [ "lymphoid enhancer factor 1" ], "offsets": [ [ 51, 77 ] ], "normalized": [] }, { "id": "PMID-10330189_T3", "type": "Protein", "text": [ "beta-catenin" ], "offsets": [ [ 199, 211 ] ], "normalized": [] }, { "id": "PMID-10330189_T4", "type": "Protein", "text": [ "beta-catenin" ], "offsets": [ [ 397, 409 ] ], "normalized": [] }, { "id": "PMID-10330189_T5", "type": "Protein", "text": [ "beta-catenin" ], "offsets": [ [ 534, 546 ] ], "normalized": [] }, { "id": "PMID-10330189_T6", "type": "Protein", "text": [ "beta-catenin" ], "offsets": [ [ 698, 710 ] ], "normalized": [] }, { "id": "PMID-10330189_T7", "type": "Protein", "text": [ "LEF-1" ], "offsets": [ [ 746, 751 ] ], "normalized": [] }, { "id": "PMID-10330189_T8", "type": "Protein", "text": [ "E-cadherin" ], "offsets": [ [ 753, 763 ] ], "normalized": [] }, { "id": "PMID-10330189_T9", "type": "Protein", "text": [ "APC" ], "offsets": [ [ 769, 772 ] ], "normalized": [] }, { "id": "PMID-10330189_T10", "type": "Protein", "text": [ "axin" ], "offsets": [ [ 781, 785 ] ], "normalized": [] }, { "id": "PMID-10330189_T11", "type": "Protein", "text": [ "beta-catenin" ], "offsets": [ [ 800, 812 ] ], "normalized": [] }, { "id": "PMID-10330189_T12", "type": "Protein", "text": [ "beta-catenin" ], "offsets": [ [ 1000, 1012 ] ], "normalized": [] }, { "id": "PMID-10330189_T13", "type": "Protein", "text": [ "beta-Catenin" ], "offsets": [ [ 1085, 1097 ] ], "normalized": [] }, { "id": "PMID-10330189_T14", "type": "Protein", "text": [ "LEF-1" ], "offsets": [ [ 1102, 1107 ] ], "normalized": [] }, { "id": "PMID-10330189_T15", "type": "Protein", "text": [ "beta-catenin" ], "offsets": [ [ 1386, 1398 ] ], "normalized": [] }, { "id": "PMID-10330189_T16", "type": "Protein", "text": [ "LEF-1" ], "offsets": [ [ 1439, 1444 ] ], "normalized": [] }, { "id": "PMID-10330189_T17", "type": "Protein", "text": [ "beta-catenin" ], "offsets": [ [ 1445, 1457 ] ], "normalized": [] }, { "id": "PMID-10330189_T18", "type": "Protein", "text": [ "VP16" ], "offsets": [ [ 1515, 1519 ] ], "normalized": [] }, { "id": "PMID-10330189_T19", "type": "Entity", "text": [ "Nuclear" ], "offsets": [ [ 0, 7 ] ], "normalized": [] }, { "id": "PMID-10330189_T24", "type": "Entity", "text": [ "nucleus" ], "offsets": [ [ 231, 238 ] ], "normalized": [] }, { "id": "PMID-10330189_T27", "type": "Entity", "text": [ "nucleus" ], "offsets": [ [ 572, 579 ] ], "normalized": [] }, { "id": "PMID-10330189_T33", "type": "Entity", "text": [ "nucleus" ], "offsets": [ [ 1030, 1037 ] ], "normalized": [] }, { "id": "PMID-10330189_T35", "type": "Entity", "text": [ "nuclear" ], "offsets": [ [ 1267, 1274 ] ], "normalized": [] }, { "id": "PMID-10330189_T37", "type": "Entity", "text": [ "nucleus" ], "offsets": [ [ 1318, 1325 ] ], "normalized": [] } ]

[ { "id": "PMID-10330189_E1", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 8, 20 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T2" }, { "role": "AtLoc", "ref_id": "PMID-10330189_T19" } ] }, { "id": "PMID-10330189_E2", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 8, 20 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T1" }, { "role": "AtLoc", "ref_id": "PMID-10330189_T19" } ] }, { "id": "PMID-10330189_E3", "type": "Binding", "trigger": { "text": [ "complexes" ], "offsets": [ [ 78, 87 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T1" }, { "role": "Theme", "ref_id": "PMID-10330189_T2" } ] }, { "id": "PMID-10330189_E4", "type": "Positive_regulation", "trigger": { "text": [ "In response to" ], "offsets": [ [ 143, 157 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_E5" } ] }, { "id": "PMID-10330189_E5", "type": "Localization", "trigger": { "text": [ "accumulates" ], "offsets": [ [ 212, 223 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T3" }, { "role": "AtLoc", "ref_id": "PMID-10330189_T24" } ] }, { "id": "PMID-10330189_E6", "type": "Positive_regulation", "trigger": { "text": [ "undergoes" ], "offsets": [ [ 410, 419 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_E4" } ] }, { "id": "PMID-10330189_E7", "type": "Localization", "trigger": { "text": [ "imported" ], "offsets": [ [ 554, 562 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T5" }, { "role": "ToLoc", "ref_id": "PMID-10330189_T27" } ] }, { "id": "PMID-10330189_E8", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 605, 612 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T5" } ] }, { "id": "PMID-10330189_E9", "type": "Localization", "trigger": { "text": [ "exported" ], "offsets": [ [ 633, 641 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T5" } ] }, { "id": "PMID-10330189_E10", "type": "Negative_regulation", "trigger": { "text": [ "disrupts" ], "offsets": [ [ 726, 734 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_E15" } ] }, { "id": "PMID-10330189_E11", "type": "Negative_regulation", "trigger": { "text": [ "disrupts" ], "offsets": [ [ 726, 734 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_E17" } ] }, { "id": "PMID-10330189_E12", "type": "Negative_regulation", "trigger": { "text": [ "disrupts" ], "offsets": [ [ 726, 734 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_E16" } ] }, { "id": "PMID-10330189_E13", "type": "Negative_regulation", "trigger": { "text": [ "disrupts" ], "offsets": [ [ 726, 734 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_E14" } ] }, { "id": "PMID-10330189_E14", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 735, 742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T6" }, { "role": "Theme", "ref_id": "PMID-10330189_T10" } ] }, { "id": "PMID-10330189_E15", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 735, 742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T6" }, { "role": "Theme", "ref_id": "PMID-10330189_T7" } ] }, { "id": "PMID-10330189_E16", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 735, 742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T6" }, { "role": "Theme", "ref_id": "PMID-10330189_T8" } ] }, { "id": "PMID-10330189_E17", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 735, 742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T6" }, { "role": "Theme", "ref_id": "PMID-10330189_T9" } ] }, { "id": "PMID-10330189_E18", "type": "Localization", "trigger": { "text": [ "localizes" ], "offsets": [ [ 1013, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T12" }, { "role": "AtLoc", "ref_id": "PMID-10330189_T33" } ] }, { "id": "PMID-10330189_E19", "type": "Localization", "trigger": { "text": [ "are" ], "offsets": [ [ 1263, 1266 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T13" }, { "role": "AtLoc", "ref_id": "PMID-10330189_T35" } ] }, { "id": "PMID-10330189_E20", "type": "Localization", "trigger": { "text": [ "are" ], "offsets": [ [ 1263, 1266 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T14" }, { "role": "AtLoc", "ref_id": "PMID-10330189_T35" } ] }, { "id": "PMID-10330189_E21", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 1282, 1294 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T13" }, { "role": "ToLoc", "ref_id": "PMID-10330189_T37" } ] }, { "id": "PMID-10330189_E22", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 1282, 1294 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T14" }, { "role": "ToLoc", "ref_id": "PMID-10330189_T37" } ] }, { "id": "PMID-10330189_E23", "type": "Positive_regulation", "trigger": { "text": [ "Excess" ], "offsets": [ [ 1379, 1385 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330189_T15" } ] } ]

[]

[]

[ { "id": "PMID-10330274__text", "type": "abstract", "text": [ "Paradoxical priming effects of IL-10 on cytokine production. \nIL-10 is a well-known immunosuppressive and/or anti-inflammatory cytokine. However, we report in vitro experimental studies in which IL-10 primed leukocytes and led to an enhanced production of tumor necrosis factor (TNF) upon further stimulation by lipopolysaccharide (LPS). Monocytes and peripheral blood mononuclear cells (PBMC) prepared from whole blood maintained for 20 h at 37 degrees C in the presence of recombinant human IL-10 had an enhanced capacity to produce TNF in response to LPS. In addition to TNF, LPS-induced IL-6 and spontaneous IL-1ra production were also enhanced. When isolated PBMC were first cultured for 20 h in the presence of IL-10 on Teflon to prevent adherence, washed to remove IL-10 and then further cultured in plastic dishes for an additional 20 h in the presence of LPS or IL-1beta, an enhanced release of TNF was observed. This was not the case when PBMC were pre-cultured in plastic multidishes in the presence of IL-10. TNF mRNA expression induced by LPS was decreased when the pre-treatment of PBMC with IL-10 was performed on plastic, whereas this was not the case when cells were pre-cultured with IL-10 on Teflon. Furthermore, NFkappaB translocation following LPS activation was higher after IL-10 pre-treatment on Teflon than on plastic. Interestingly, an enhanced frequency of CD16 and CD68(+) cells among the CD14(+) cells was observed in the presence of IL-10, independently of the pre-culture conditions of the PBMC. Altogether, these results indicate that the IL-10-induced up-regulation of cytokine production depends on the prevention of monocyte adherence by red cells in the whole blood assays or by cultures of PBMC on Teflon. In contrast, the adherence parameter has no effect on the IL-10-induced modulation of some monocyte surface markers. " ], "offsets": [ [ 0, 1860 ] ] } ]

[ { "id": "PMID-10330274_T1", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 31, 36 ] ], "normalized": [] }, { "id": "PMID-10330274_T2", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 62, 67 ] ], "normalized": [] }, { "id": "PMID-10330274_T3", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 195, 200 ] ], "normalized": [] }, { "id": "PMID-10330274_T4", "type": "Protein", "text": [ "tumor necrosis factor" ], "offsets": [ [ 256, 277 ] ], "normalized": [] }, { "id": "PMID-10330274_T5", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 279, 282 ] ], "normalized": [] }, { "id": "PMID-10330274_T6", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 493, 498 ] ], "normalized": [] }, { "id": "PMID-10330274_T7", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 535, 538 ] ], "normalized": [] }, { "id": "PMID-10330274_T8", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 574, 577 ] ], "normalized": [] }, { "id": "PMID-10330274_T9", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 591, 595 ] ], "normalized": [] }, { "id": "PMID-10330274_T10", "type": "Protein", "text": [ "IL-1ra" ], "offsets": [ [ 612, 618 ] ], "normalized": [] }, { "id": "PMID-10330274_T11", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 717, 722 ] ], "normalized": [] }, { "id": "PMID-10330274_T12", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 772, 777 ] ], "normalized": [] }, { "id": "PMID-10330274_T13", "type": "Protein", "text": [ "IL-1beta" ], "offsets": [ [ 871, 879 ] ], "normalized": [] }, { "id": "PMID-10330274_T14", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 904, 907 ] ], "normalized": [] }, { "id": "PMID-10330274_T15", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1014, 1019 ] ], "normalized": [] }, { "id": "PMID-10330274_T16", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1106, 1111 ] ], "normalized": [] }, { "id": "PMID-10330274_T17", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1202, 1207 ] ], "normalized": [] }, { "id": "PMID-10330274_T18", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1297, 1302 ] ], "normalized": [] }, { "id": "PMID-10330274_T19", "type": "Protein", "text": [ "CD16" ], "offsets": [ [ 1384, 1388 ] ], "normalized": [] }, { "id": "PMID-10330274_T20", "type": "Protein", "text": [ "CD68" ], "offsets": [ [ 1393, 1397 ] ], "normalized": [] }, { "id": "PMID-10330274_T21", "type": "Protein", "text": [ "CD14" ], "offsets": [ [ 1417, 1421 ] ], "normalized": [] }, { "id": "PMID-10330274_T22", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1463, 1468 ] ], "normalized": [] }, { "id": "PMID-10330274_T23", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1571, 1576 ] ], "normalized": [] }, { "id": "PMID-10330274_T24", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1801, 1806 ] ], "normalized": [] } ]

[ { "id": "PMID-10330274_E1", "type": "Positive_regulation", "trigger": { "text": [ "led to an enhanced" ], "offsets": [ [ 223, 241 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330274_E3" } ] }, { "id": "PMID-10330274_E2", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 242, 252 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330274_T5" } ] }, { "id": "PMID-10330274_E3", "type": "Positive_regulation", "trigger": { "text": [ "upon" ], "offsets": [ [ 284, 288 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330274_E2" } ] }, { "id": "PMID-10330274_E4", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 506, 514 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330274_E6" } ] }, { "id": "PMID-10330274_E5", "type": "Gene_expression", "trigger": { "text": [ "produce" ], "offsets": [ [ 527, 534 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330274_T7" } ] }, { "id": "PMID-10330274_E6", "type": "Positive_regulation", "trigger": { "text": [ "in response to" ], "offsets": [ [ 539, 553 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330274_E5" } ] }, { "id": "PMID-10330274_E7", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 583, 590 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330274_E9" } ] }, { "id": "PMID-10330274_E8", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 619, 629 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330274_T10" } ] }, { "id": "PMID-10330274_E9", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 619, 629 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330274_T9" } ] }, { "id": "PMID-10330274_E10", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 640, 648 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330274_E8" } ] }, { "id": "PMID-10330274_E11", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 640, 648 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330274_E7" } ] }, { "id": "PMID-10330274_E12", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 884, 892 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330274_E13" } ] }, { "id": "PMID-10330274_E13", "type": "Localization", "trigger": { "text": [ "release" ], "offsets": [ [ 893, 900 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330274_T14" } ] }, { "id": "PMID-10330274_E14", "type": "Positive_regulation", "trigger": { "text": [ "not" ], "offsets": [ [ 931, 934 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10330274_E13" } ] } ]

[ { "id": "PMID-10330274_1", "entity_ids": [ "PMID-10330274_T5", "PMID-10330274_T4" ] } ]

[]

[ { "id": "PMID-10331989__text", "type": "abstract", "text": [ "Different sequence requirements for expression in erythroid and megakaryocytic cells within a regulatory element upstream of the GATA-1 gene. \nThe lineage-restricted transcription factor GATA-1 is required for differentiation of erythroid and megakaryocytic cells. We have localized a 317 base pair cis-acting regulatory element, HS I, associated with a hematopoietic-specific DNase I hypersensitive site, which lies approx. 3.7 kilobases upstream of the murine hematopoietic-specific GATA-1 IE promoter. HS I directs high-level expression of reporter GATA-1/lacZ genes to primitive and definitive erythroid cells and megakaryocytes in transgenic mice. Comparative sequence analysis of HS I between human and mouse shows approx. 63% nucleotide identity with a more conserved core of 169 base pairs (86% identity). This core contains a GATA site separated by 10 base pairs from an E-box motif. The composite motif binds a multi-protein hematopoietic-specific transcription factor complex which includes GATA-1, SCL/tal-1, E2A, Lmo2 and Ldb-1. Point mutations of the GATA site abolishes HS I function, whereas mutation of the E-box motif still allows reporter gene expression in both lineages. Strict dependence of HS I activity on a GATA site implies that assembly of a protein complex containing a GATA-factor, presumably GATA-1 or GATA-2, is critical to activating or maintaining its function. Further dissection of the 317 base pair region demonstrates that, whereas all 317 base pairs are required for expression in megakaryocytes, only the 5' 62 base pairs are needed for erythroid-specific reporter expression. These findings demonstrate differential lineage requirements for expression within the HS I element. " ], "offsets": [ [ 0, 1717 ] ] } ]

[ { "id": "PMID-10331989_T1", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 129, 135 ] ], "normalized": [] }, { "id": "PMID-10331989_T2", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 187, 193 ] ], "normalized": [] }, { "id": "PMID-10331989_T3", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 485, 491 ] ], "normalized": [] }, { "id": "PMID-10331989_T4", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 552, 558 ] ], "normalized": [] }, { "id": "PMID-10331989_T5", "type": "Protein", "text": [ "lacZ" ], "offsets": [ [ 559, 563 ] ], "normalized": [] }, { "id": "PMID-10331989_T6", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 1002, 1008 ] ], "normalized": [] }, { "id": "PMID-10331989_T7", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 1010, 1013 ] ], "normalized": [] }, { "id": "PMID-10331989_T8", "type": "Protein", "text": [ "tal-1" ], "offsets": [ [ 1014, 1019 ] ], "normalized": [] }, { "id": "PMID-10331989_T9", "type": "Protein", "text": [ "E2A" ], "offsets": [ [ 1021, 1024 ] ], "normalized": [] }, { "id": "PMID-10331989_T10", "type": "Protein", "text": [ "Lmo2" ], "offsets": [ [ 1026, 1030 ] ], "normalized": [] }, { "id": "PMID-10331989_T11", "type": "Protein", "text": [ "Ldb-1" ], "offsets": [ [ 1035, 1040 ] ], "normalized": [] }, { "id": "PMID-10331989_T12", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 1322, 1328 ] ], "normalized": [] }, { "id": "PMID-10331989_T13", "type": "Protein", "text": [ "GATA-2" ], "offsets": [ [ 1332, 1338 ] ], "normalized": [] } ]

[ { "id": "PMID-10331989_E1", "type": "Positive_regulation", "trigger": { "text": [ "requirements" ], "offsets": [ [ 19, 31 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10331989_E2" } ] }, { "id": "PMID-10331989_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 36, 46 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10331989_T1" } ] }, { "id": "PMID-10331989_E3", "type": "Positive_regulation", "trigger": { "text": [ "directs" ], "offsets": [ [ 510, 517 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10331989_E4" } ] }, { "id": "PMID-10331989_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 529, 539 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10331989_T5" } ] }, { "id": "PMID-10331989_E5", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 913, 918 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10331989_T6" } ] }, { "id": "PMID-10331989_E6", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 913, 918 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10331989_T9" } ] }, { "id": "PMID-10331989_E7", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 913, 918 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10331989_T7" } ] }, { "id": "PMID-10331989_E8", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 913, 918 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10331989_T10" } ] }, { "id": "PMID-10331989_E9", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 913, 918 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10331989_T11" } ] }, { "id": "PMID-10331989_E10", "type": "Binding", "trigger": { "text": [ "assembly of a protein complex" ], "offsets": [ [ 1255, 1284 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10331989_T13" } ] }, { "id": "PMID-10331989_E11", "type": "Binding", "trigger": { "text": [ "assembly of a protein complex" ], "offsets": [ [ 1255, 1284 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10331989_T12" } ] } ]

[ { "id": "PMID-10331989_1", "entity_ids": [ "PMID-10331989_T7", "PMID-10331989_T8" ] } ]

[]

[ { "id": "PMID-10339475__text", "type": "abstract", "text": [ "Monocyte arrest and transmigration on inflamed endothelium in shear flow is inhibited by adenovirus-mediated gene transfer of IkappaB-alpha. \nMobilization of nuclear factor-kappaB (NF-kappaB) activates transcription of genes encoding endothelial adhesion molecules and chemokines that contribute to monocyte infiltration critical in atherogenesis. Inhibition of NF-kappaB has been achieved by pharmacological and genetic approaches; however, monocyte interactions with activated endothelium in shear flow following gene transfer of the NF-kappaB inhibitor IkappaB-alpha have not been studied. We found that overexpression of IkappaB-alpha in endothelial cells using a recombinant adenovirus prevented tumor necrosis factor-alpha (TNF-alpha)-induced degradation of IkappaB-alpha and suppressed the upregulation of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin mRNA and surface protein expression and the upregulation of transcripts for the chemokines monocyte chemoattractant protein 1 (MCP-1) and growth-related activity-alpha (GRO-alpha) by TNF-alpha. This was associated with a reduction in endothelial MCP-1 secretion and GRO-alpha immobilization. Adhesion assays under physiological shear flow conditions showed that firm arrest, spreading, and transmigration of monocytes on TNF-alpha-activated endothelium was markedly inhibited by IkappaB-alpha overexpression. Inhibition with monoclonal antibodies and peptide antagonists inferred that this was due to reduced expression of Ig integrin ligand as well as of chemokines specifically involved in these events. In contrast, rolling of monocytes was increased by IkappaB-alpha transfer and was partly mediated by P-selectin; however, it appeared to be unaffected by the inhibition of E-selectin induction. Thus, our data provide novel evidence that selective modulation of NF-kappaB by adenoviral transfer of IkappaB-alpha impairs the expression of multiple endothelial gene products required for subsequent monocyte arrest and emigration in shear flow and thus for monocyte infiltration in atherosclerotic plaques. " ], "offsets": [ [ 0, 2126 ] ] } ]

[ { "id": "PMID-10339475_T1", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 126, 139 ] ], "normalized": [] }, { "id": "PMID-10339475_T2", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 556, 569 ] ], "normalized": [] }, { "id": "PMID-10339475_T3", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 625, 638 ] ], "normalized": [] }, { "id": "PMID-10339475_T4", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 701, 728 ] ], "normalized": [] }, { "id": "PMID-10339475_T5", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 730, 739 ] ], "normalized": [] }, { "id": "PMID-10339475_T6", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 764, 777 ] ], "normalized": [] }, { "id": "PMID-10339475_T7", "type": "Protein", "text": [ "vascular cell adhesion molecule-1" ], "offsets": [ [ 813, 846 ] ], "normalized": [] }, { "id": "PMID-10339475_T8", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 848, 854 ] ], "normalized": [] }, { "id": "PMID-10339475_T9", "type": "Protein", "text": [ "intercellular adhesion molecule-1" ], "offsets": [ [ 857, 890 ] ], "normalized": [] }, { "id": "PMID-10339475_T10", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 892, 898 ] ], "normalized": [] }, { "id": "PMID-10339475_T11", "type": "Protein", "text": [ "E-selectin" ], "offsets": [ [ 905, 915 ] ], "normalized": [] }, { "id": "PMID-10339475_T12", "type": "Protein", "text": [ "monocyte chemoattractant protein 1" ], "offsets": [ [ 1007, 1041 ] ], "normalized": [] }, { "id": "PMID-10339475_T13", "type": "Protein", "text": [ "MCP-1" ], "offsets": [ [ 1043, 1048 ] ], "normalized": [] }, { "id": "PMID-10339475_T14", "type": "Protein", "text": [ "growth-related activity-alpha" ], "offsets": [ [ 1054, 1083 ] ], "normalized": [] }, { "id": "PMID-10339475_T15", "type": "Protein", "text": [ "GRO-alpha" ], "offsets": [ [ 1085, 1094 ] ], "normalized": [] }, { "id": "PMID-10339475_T16", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1099, 1108 ] ], "normalized": [] }, { "id": "PMID-10339475_T17", "type": "Protein", "text": [ "MCP-1" ], "offsets": [ [ 1162, 1167 ] ], "normalized": [] }, { "id": "PMID-10339475_T18", "type": "Protein", "text": [ "GRO-alpha" ], "offsets": [ [ 1182, 1191 ] ], "normalized": [] }, { "id": "PMID-10339475_T19", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1337, 1346 ] ], "normalized": [] }, { "id": "PMID-10339475_T20", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1395, 1408 ] ], "normalized": [] }, { "id": "PMID-10339475_T21", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1673, 1686 ] ], "normalized": [] }, { "id": "PMID-10339475_T22", "type": "Protein", "text": [ "P-selectin" ], "offsets": [ [ 1723, 1733 ] ], "normalized": [] }, { "id": "PMID-10339475_T23", "type": "Protein", "text": [ "E-selectin" ], "offsets": [ [ 1794, 1804 ] ], "normalized": [] }, { "id": "PMID-10339475_T24", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1919, 1932 ] ], "normalized": [] } ]

[ { "id": "PMID-10339475_E1", "type": "Gene_expression", "trigger": { "text": [ "gene transfer" ], "offsets": [ [ 109, 122 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T1" } ] }, { "id": "PMID-10339475_E2", "type": "Positive_regulation", "trigger": { "text": [ "gene transfer" ], "offsets": [ [ 109, 122 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E1" } ] }, { "id": "PMID-10339475_E3", "type": "Positive_regulation", "trigger": { "text": [ "following" ], "offsets": [ [ 505, 514 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E4" } ] }, { "id": "PMID-10339475_E4", "type": "Gene_expression", "trigger": { "text": [ "gene transfer" ], "offsets": [ [ 515, 528 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T2" } ] }, { "id": "PMID-10339475_E5", "type": "Positive_regulation", "trigger": { "text": [ "gene transfer" ], "offsets": [ [ 515, 528 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E4" } ] }, { "id": "PMID-10339475_E6", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 607, 621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T3" } ] }, { "id": "PMID-10339475_E7", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 607, 621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E6" } ] }, { "id": "PMID-10339475_E8", "type": "Negative_regulation", "trigger": { "text": [ "prevented" ], "offsets": [ [ 691, 700 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E10" }, { "role": "Cause", "ref_id": "PMID-10339475_E7" } ] }, { "id": "PMID-10339475_E9", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 741, 748 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E10" }, { "role": "Cause", "ref_id": "PMID-10339475_T5" } ] }, { "id": "PMID-10339475_E10", "type": "Protein_catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 749, 760 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T6" } ] }, { "id": "PMID-10339475_E11", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 782, 792 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E20" }, { "role": "Cause", "ref_id": "PMID-10339475_E6" } ] }, { "id": "PMID-10339475_E12", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 782, 792 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E22" }, { "role": "Cause", "ref_id": "PMID-10339475_E6" } ] }, { "id": "PMID-10339475_E13", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 782, 792 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E24" }, { "role": "Cause", "ref_id": "PMID-10339475_E6" } ] }, { "id": "PMID-10339475_E14", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 782, 792 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E19" }, { "role": "Cause", "ref_id": "PMID-10339475_E6" } ] }, { "id": "PMID-10339475_E15", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 782, 792 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E32" }, { "role": "Cause", "ref_id": "PMID-10339475_E6" } ] }, { "id": "PMID-10339475_E16", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 782, 792 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E31" }, { "role": "Cause", "ref_id": "PMID-10339475_E6" } ] }, { "id": "PMID-10339475_E17", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 782, 792 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E23" }, { "role": "Cause", "ref_id": "PMID-10339475_E6" } ] }, { "id": "PMID-10339475_E18", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 782, 792 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E21" }, { "role": "Cause", "ref_id": "PMID-10339475_E6" } ] }, { "id": "PMID-10339475_E19", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 797, 809 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E25" } ] }, { "id": "PMID-10339475_E20", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 797, 809 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E30" } ] }, { "id": "PMID-10339475_E21", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 797, 809 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E29" } ] }, { "id": "PMID-10339475_E22", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 797, 809 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E27" } ] }, { "id": "PMID-10339475_E23", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 797, 809 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E28" } ] }, { "id": "PMID-10339475_E24", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 797, 809 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E26" } ] }, { "id": "PMID-10339475_E25", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 941, 951 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T8" } ] }, { "id": "PMID-10339475_E26", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 941, 951 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T11" } ] }, { "id": "PMID-10339475_E27", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 941, 951 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T8" } ] }, { "id": "PMID-10339475_E28", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 941, 951 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T10" } ] }, { "id": "PMID-10339475_E29", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 941, 951 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T11" } ] }, { "id": "PMID-10339475_E30", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 941, 951 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T10" } ] }, { "id": "PMID-10339475_E31", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 960, 972 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E34" }, { "role": "Cause", "ref_id": "PMID-10339475_T16" } ] }, { "id": "PMID-10339475_E32", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 960, 972 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E33" }, { "role": "Cause", "ref_id": "PMID-10339475_T16" } ] }, { "id": "PMID-10339475_E33", "type": "Transcription", "trigger": { "text": [ "transcripts" ], "offsets": [ [ 976, 987 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T15" } ] }, { "id": "PMID-10339475_E34", "type": "Transcription", "trigger": { "text": [ "transcripts" ], "offsets": [ [ 976, 987 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T13" } ] }, { "id": "PMID-10339475_E35", "type": "Negative_regulation", "trigger": { "text": [ "reduction" ], "offsets": [ [ 1137, 1146 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E36" } ] }, { "id": "PMID-10339475_E36", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 1168, 1177 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T17" } ] }, { "id": "PMID-10339475_E37", "type": "Localization", "trigger": { "text": [ "immobilization" ], "offsets": [ [ 1192, 1206 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T18" } ] }, { "id": "PMID-10339475_E38", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1409, 1423 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T20" } ] }, { "id": "PMID-10339475_E39", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1409, 1423 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E38" } ] }, { "id": "PMID-10339475_E40", "type": "Positive_regulation", "trigger": { "text": [ "transfer" ], "offsets": [ [ 1687, 1695 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E41" } ] }, { "id": "PMID-10339475_E41", "type": "Gene_expression", "trigger": { "text": [ "transfer" ], "offsets": [ [ 1687, 1695 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T21" } ] }, { "id": "PMID-10339475_E42", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1780, 1790 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E43" } ] }, { "id": "PMID-10339475_E43", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1805, 1814 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T23" } ] }, { "id": "PMID-10339475_E44", "type": "Gene_expression", "trigger": { "text": [ "transfer" ], "offsets": [ [ 1907, 1915 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_T24" } ] }, { "id": "PMID-10339475_E45", "type": "Positive_regulation", "trigger": { "text": [ "transfer" ], "offsets": [ [ 1907, 1915 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10339475_E44" } ] } ]

[ { "id": "PMID-10339475_1", "entity_ids": [ "PMID-10339475_T15", "PMID-10339475_T14" ] }, { "id": "PMID-10339475_2", "entity_ids": [ "PMID-10339475_T13", "PMID-10339475_T12" ] }, { "id": "PMID-10339475_3", "entity_ids": [ "PMID-10339475_T8", "PMID-10339475_T7" ] }, { "id": "PMID-10339475_4", "entity_ids": [ "PMID-10339475_T10", "PMID-10339475_T9" ] }, { "id": "PMID-10339475_5", "entity_ids": [ "PMID-10339475_T5", "PMID-10339475_T4" ] } ]

[]

[ { "id": "PMID-10347175__text", "type": "abstract", "text": [ "SLP-76 and Vav function in separate, but overlapping pathways to augment interleukin-2 promoter activity. \nSLP-76 and Vav, two hematopoietic cell specific molecules, are critical for T cell development and activation. Following T cell antigen receptor stimulation, SLP-76 and Vav both undergo tyrosine phosphorylation and associate with each other via the SH2 domain of Vav and phosphorylated tyrosines of SLP-76. Furthermore, SLP-76 and Vav have a synergistic effect on interleukin (IL)-2 promoter activity in T cells. In this report, we show that two tyrosines, Tyr-113 and Tyr-128, of SLP-76 are required for its binding to Vav, both in vitro and in intact cells. Surprisingly, we find also that the interaction between SLP-76 and Vav is not required for their cooperation in augmenting IL-2 promoter activity, as the two molecules appear to function in different signaling pathways upstream of IL-2 gene expression. Overexpression of SLP-76 in the Jurkat T cell line potentiates the activities of both nuclear factor of activated T cells and AP-1 transcription factors. In contrast, overexpression of Vav leads to enhanced nuclear factor of activated T cells activity without affecting AP-1. Additionally, overexpression of Vav, but not SLP-76, augments CD28-induced IL-2 promoter activity. These findings suggest that the synergy between SLP-76 and Vav in regulating IL-2 gene expression reflects the cooperation between different signaling pathways. " ], "offsets": [ [ 0, 1456 ] ] } ]

[ { "id": "PMID-10347175_T1", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "PMID-10347175_T2", "type": "Protein", "text": [ "Vav" ], "offsets": [ [ 11, 14 ] ], "normalized": [] }, { "id": "PMID-10347175_T3", "type": "Protein", "text": [ "interleukin-2" ], "offsets": [ [ 73, 86 ] ], "normalized": [] }, { "id": "PMID-10347175_T4", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 107, 113 ] ], "normalized": [] }, { "id": "PMID-10347175_T5", "type": "Protein", "text": [ "Vav" ], "offsets": [ [ 118, 121 ] ], "normalized": [] }, { "id": "PMID-10347175_T6", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 265, 271 ] ], "normalized": [] }, { "id": "PMID-10347175_T7", "type": "Protein", "text": [ "Vav" ], "offsets": [ [ 276, 279 ] ], "normalized": [] }, { "id": "PMID-10347175_T8", "type": "Protein", "text": [ "Vav" ], "offsets": [ [ 370, 373 ] ], "normalized": [] }, { "id": "PMID-10347175_T9", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 406, 412 ] ], "normalized": [] }, { "id": "PMID-10347175_T10", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 427, 433 ] ], "normalized": [] }, { "id": "PMID-10347175_T11", "type": "Protein", "text": [ "Vav" ], "offsets": [ [ 438, 441 ] ], "normalized": [] }, { "id": "PMID-10347175_T12", "type": "Protein", "text": [ "interleukin (IL)-2" ], "offsets": [ [ 471, 489 ] ], "normalized": [] }, { "id": "PMID-10347175_T13", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 588, 594 ] ], "normalized": [] }, { "id": "PMID-10347175_T14", "type": "Protein", "text": [ "Vav" ], "offsets": [ [ 627, 630 ] ], "normalized": [] }, { "id": "PMID-10347175_T15", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 723, 729 ] ], "normalized": [] }, { "id": "PMID-10347175_T16", "type": "Protein", "text": [ "Vav" ], "offsets": [ [ 734, 737 ] ], "normalized": [] }, { "id": "PMID-10347175_T17", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 790, 794 ] ], "normalized": [] }, { "id": "PMID-10347175_T18", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 898, 902 ] ], "normalized": [] }, { "id": "PMID-10347175_T19", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 938, 944 ] ], "normalized": [] }, { "id": "PMID-10347175_T20", "type": "Protein", "text": [ "Vav" ], "offsets": [ [ 1105, 1108 ] ], "normalized": [] }, { "id": "PMID-10347175_T21", "type": "Protein", "text": [ "Vav" ], "offsets": [ [ 1228, 1231 ] ], "normalized": [] }, { "id": "PMID-10347175_T22", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 1241, 1247 ] ], "normalized": [] }, { "id": "PMID-10347175_T23", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 1258, 1262 ] ], "normalized": [] }, { "id": "PMID-10347175_T24", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1271, 1275 ] ], "normalized": [] }, { "id": "PMID-10347175_T25", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 1343, 1349 ] ], "normalized": [] }, { "id": "PMID-10347175_T26", "type": "Protein", "text": [ "Vav" ], "offsets": [ [ 1354, 1357 ] ], "normalized": [] }, { "id": "PMID-10347175_T27", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1372, 1376 ] ], "normalized": [] }, { "id": "PMID-10347175_T29", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 87, 95 ] ], "normalized": [] }, { "id": "PMID-10347175_T31", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 293, 301 ] ], "normalized": [] }, { "id": "PMID-10347175_T34", "type": "Entity", "text": [ "SH2 domain" ], "offsets": [ [ 356, 366 ] ], "normalized": [] }, { "id": "PMID-10347175_T36", "type": "Entity", "text": [ "tyrosines" ], "offsets": [ [ 393, 402 ] ], "normalized": [] }, { "id": "PMID-10347175_T38", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 490, 498 ] ], "normalized": [] }, { "id": "PMID-10347175_T44", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 795, 803 ] ], "normalized": [] }, { "id": "PMID-10347175_T55", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1276, 1284 ] ], "normalized": [] } ]

[ { "id": "PMID-10347175_E1", "type": "Positive_regulation", "trigger": { "text": [ "augment" ], "offsets": [ [ 65, 72 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T3" }, { "role": "Cause", "ref_id": "PMID-10347175_T1" }, { "role": "Site", "ref_id": "PMID-10347175_T29" } ] }, { "id": "PMID-10347175_E2", "type": "Positive_regulation", "trigger": { "text": [ "augment" ], "offsets": [ [ 65, 72 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T3" }, { "role": "Cause", "ref_id": "PMID-10347175_T2" }, { "role": "Site", "ref_id": "PMID-10347175_T29" } ] }, { "id": "PMID-10347175_E3", "type": "Positive_regulation", "trigger": { "text": [ "Following" ], "offsets": [ [ 218, 227 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_E5" } ] }, { "id": "PMID-10347175_E4", "type": "Positive_regulation", "trigger": { "text": [ "Following" ], "offsets": [ [ 218, 227 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_E6" } ] }, { "id": "PMID-10347175_E5", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 302, 317 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T7" }, { "role": "Site", "ref_id": "PMID-10347175_T31" } ] }, { "id": "PMID-10347175_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 302, 317 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T6" }, { "role": "Site", "ref_id": "PMID-10347175_T31" } ] }, { "id": "PMID-10347175_E7", "type": "Binding", "trigger": { "text": [ "associate" ], "offsets": [ [ 322, 331 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T8" }, { "role": "Theme", "ref_id": "PMID-10347175_T9" }, { "role": "Site", "ref_id": "PMID-10347175_T34" } ] }, { "id": "PMID-10347175_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 378, 392 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T9" }, { "role": "Site", "ref_id": "PMID-10347175_T36" } ] }, { "id": "PMID-10347175_E9", "type": "Positive_regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 461, 467 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T12" }, { "role": "Cause", "ref_id": "PMID-10347175_T11" }, { "role": "Site", "ref_id": "PMID-10347175_T38" } ] }, { "id": "PMID-10347175_E10", "type": "Positive_regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 461, 467 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T12" }, { "role": "Cause", "ref_id": "PMID-10347175_T10" }, { "role": "Site", "ref_id": "PMID-10347175_T38" } ] }, { "id": "PMID-10347175_E11", "type": "Regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 599, 607 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_E12" } ] }, { "id": "PMID-10347175_E12", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 616, 623 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T13" }, { "role": "Theme", "ref_id": "PMID-10347175_T14" } ] }, { "id": "PMID-10347175_E13", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 703, 714 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T15" }, { "role": "Theme", "ref_id": "PMID-10347175_T16" } ] }, { "id": "PMID-10347175_E14", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 745, 753 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_E16" }, { "role": "Cause", "ref_id": "PMID-10347175_E13" } ] }, { "id": "PMID-10347175_E15", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 745, 753 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_E17" }, { "role": "Cause", "ref_id": "PMID-10347175_E13" } ] }, { "id": "PMID-10347175_E16", "type": "Positive_regulation", "trigger": { "text": [ "augmenting" ], "offsets": [ [ 779, 789 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T17" }, { "role": "Cause", "ref_id": "PMID-10347175_T16" }, { "role": "Site", "ref_id": "PMID-10347175_T44" } ] }, { "id": "PMID-10347175_E17", "type": "Positive_regulation", "trigger": { "text": [ "augmenting" ], "offsets": [ [ 779, 789 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T17" }, { "role": "Cause", "ref_id": "PMID-10347175_T15" }, { "role": "Site", "ref_id": "PMID-10347175_T44" } ] }, { "id": "PMID-10347175_E18", "type": "Positive_regulation", "trigger": { "text": [ "upstream" ], "offsets": [ [ 886, 894 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_E19" } ] }, { "id": "PMID-10347175_E19", "type": "Gene_expression", "trigger": { "text": [ "gene expression" ], "offsets": [ [ 903, 918 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T18" } ] }, { "id": "PMID-10347175_E20", "type": "Positive_regulation", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 920, 934 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_E21" } ] }, { "id": "PMID-10347175_E21", "type": "Gene_expression", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 920, 934 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T19" } ] }, { "id": "PMID-10347175_E22", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1087, 1101 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_E23" } ] }, { "id": "PMID-10347175_E23", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1087, 1101 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T20" } ] }, { "id": "PMID-10347175_E24", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1210, 1224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T22" } ] }, { "id": "PMID-10347175_E25", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1210, 1224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_E26" } ] }, { "id": "PMID-10347175_E26", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1210, 1224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T21" } ] }, { "id": "PMID-10347175_E27", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1210, 1224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_E24" } ] }, { "id": "PMID-10347175_E28", "type": "Positive_regulation", "trigger": { "text": [ "augments" ], "offsets": [ [ 1249, 1257 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_E30" }, { "role": "Cause", "ref_id": "PMID-10347175_E27" } ] }, { "id": "PMID-10347175_E29", "type": "Positive_regulation", "trigger": { "text": [ "augments" ], "offsets": [ [ 1249, 1257 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_E30" }, { "role": "Cause", "ref_id": "PMID-10347175_E25" } ] }, { "id": "PMID-10347175_E30", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1263, 1270 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T24" }, { "role": "Cause", "ref_id": "PMID-10347175_T23" }, { "role": "Site", "ref_id": "PMID-10347175_T55" } ] }, { "id": "PMID-10347175_E31", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 1361, 1371 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_E33" }, { "role": "Cause", "ref_id": "PMID-10347175_T25" } ] }, { "id": "PMID-10347175_E32", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 1361, 1371 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_E33" }, { "role": "Cause", "ref_id": "PMID-10347175_T26" } ] }, { "id": "PMID-10347175_E33", "type": "Gene_expression", "trigger": { "text": [ "gene expression" ], "offsets": [ [ 1377, 1392 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10347175_T27" } ] } ]

[]

[]

[ { "id": "PMID-10349513__text", "type": "abstract", "text": [ "Targeted remodeling of human beta-globin promoter chromatin structure produces increased expression and decreased silencing. \nThe chromatin structure of the human beta-globin gene locus assumes a transcriptionally-active conformation in erythroid cells. One feature of this chromatin reorganization is the formation of DNase 1 hypersensitive sites in the regions of active globin gene promoters. This reorganization requires the globin locus control region and is associated with normal expression of the beta-like globin genes. To determine whether it is possible to artificially enhance the opening of the chromatin structure of a minimal beta-globin promoter, we placed a 101bp, erythroid-specific DNase 1 hypersensitive site-forming element (HSFE) immediately upstream of the beta-globin promoter and gene. This element includes binding sites for NF-E2, AP-1, GATA-1 and Sp-1. Constructs were stably transfected into murine erythroleukemia cells and promoter chromatin structure and gene expression were analyzed. The HSFE induced an area of enhanced DNase 1 hypersensitivity extending from the transcriptional start site to -300bp of the artificial promoter and significantly increased the proportion of beta-globin promoters in an open chromatin configuration. This remodeling of promoter chromatin structure resulted in 3-fold increases in beta-globin gene transcription and induction, and inhibited long-term beta-globin gene silencing. These results indicate that a relatively small cis-acting element is able to enhance remodeling of promoter chromatin structure resulting in increased beta-globin gene expression. " ], "offsets": [ [ 0, 1625 ] ] } ]

[ { "id": "PMID-10349513_T1", "type": "Protein", "text": [ "beta-globin" ], "offsets": [ [ 29, 40 ] ], "normalized": [] }, { "id": "PMID-10349513_T2", "type": "Protein", "text": [ "beta-globin" ], "offsets": [ [ 163, 174 ] ], "normalized": [] }, { "id": "PMID-10349513_T3", "type": "Protein", "text": [ "beta-globin" ], "offsets": [ [ 641, 652 ] ], "normalized": [] }, { "id": "PMID-10349513_T4", "type": "Protein", "text": [ "beta-globin" ], "offsets": [ [ 780, 791 ] ], "normalized": [] }, { "id": "PMID-10349513_T5", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 864, 870 ] ], "normalized": [] }, { "id": "PMID-10349513_T6", "type": "Protein", "text": [ "Sp-1" ], "offsets": [ [ 875, 879 ] ], "normalized": [] }, { "id": "PMID-10349513_T7", "type": "Protein", "text": [ "DNase 1" ], "offsets": [ [ 1055, 1062 ] ], "normalized": [] }, { "id": "PMID-10349513_T8", "type": "Protein", "text": [ "beta-globin" ], "offsets": [ [ 1209, 1220 ] ], "normalized": [] }, { "id": "PMID-10349513_T9", "type": "Protein", "text": [ "beta-globin" ], "offsets": [ [ 1347, 1358 ] ], "normalized": [] }, { "id": "PMID-10349513_T10", "type": "Protein", "text": [ "beta-globin" ], "offsets": [ [ 1417, 1428 ] ], "normalized": [] }, { "id": "PMID-10349513_T11", "type": "Protein", "text": [ "beta-globin" ], "offsets": [ [ 1596, 1607 ] ], "normalized": [] }, { "id": "PMID-10349513_T16", "type": "Entity", "text": [ "promoters" ], "offsets": [ [ 1221, 1230 ] ], "normalized": [] } ]

[ { "id": "PMID-10349513_E1", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 79, 88 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10349513_E2" } ] }, { "id": "PMID-10349513_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 89, 99 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10349513_T1" } ] }, { "id": "PMID-10349513_E3", "type": "Transcription", "trigger": { "text": [ "transcriptionally-active" ], "offsets": [ [ 196, 220 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10349513_T2" } ] }, { "id": "PMID-10349513_E4", "type": "Positive_regulation", "trigger": { "text": [ "increased the proportion" ], "offsets": [ [ 1181, 1205 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10349513_T8" }, { "role": "Site", "ref_id": "PMID-10349513_T16" } ] }, { "id": "PMID-10349513_E5", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 1334, 1343 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10349513_E8" } ] }, { "id": "PMID-10349513_E6", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 1334, 1343 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10349513_E7" } ] }, { "id": "PMID-10349513_E7", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1364, 1377 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10349513_T9" } ] }, { "id": "PMID-10349513_E8", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1382, 1391 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10349513_T9" } ] }, { "id": "PMID-10349513_E9", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1586, 1595 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10349513_E10" } ] }, { "id": "PMID-10349513_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1613, 1623 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10349513_T11" } ] } ]

[]

[]

[ { "id": "PMID-10352258__text", "type": "abstract", "text": [ "In vivo inhibition of NF-kappa B in T-lineage cells leads to a dramatic decrease in cell proliferation and cytokine production and to increased cell apoptosis in response to mitogenic stimuli, but not to abnormal thymopoiesis. \nTo understand the role of NF-kappa B complexes in T cell development and activation, we have generated transgenic mice in which RelA and c-Rel complexes were selectively inhibited in the T-lineage cells by specific expression of a trans-dominant form of I kappa B alpha. Transgene expression did not affect the thymic development, but led to lowered numbers of splenic T cells and to a dramatic decrease in the ex vivo proliferative response of splenic T lymphocytes. Analysis of IL-2 and IL-2R alpha expression demonstrated that the perturbation of the proliferation response was not attributable to an abnormal expression of these genes. In contrast, expression of IL-4, IL-10, and IFN-gamma was strongly inhibited in the transgenic T cells. The proliferative deficiency of the transgenic T cells was associated with an increased apoptosis. These results point out the involvement of NF-kappa B/Rel family proteins in growth signaling pathways by either regulating proteins involved in the IL-2 signaling or by functionally interfering with the cell cycle progression. " ], "offsets": [ [ 0, 1299 ] ] } ]

[ { "id": "PMID-10352258_T1", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 356, 360 ] ], "normalized": [] }, { "id": "PMID-10352258_T2", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 365, 370 ] ], "normalized": [] }, { "id": "PMID-10352258_T3", "type": "Protein", "text": [ "I kappa B alpha" ], "offsets": [ [ 482, 497 ] ], "normalized": [] }, { "id": "PMID-10352258_T4", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 708, 712 ] ], "normalized": [] }, { "id": "PMID-10352258_T5", "type": "Protein", "text": [ "IL-2R alpha" ], "offsets": [ [ 717, 728 ] ], "normalized": [] }, { "id": "PMID-10352258_T6", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 895, 899 ] ], "normalized": [] }, { "id": "PMID-10352258_T7", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 901, 906 ] ], "normalized": [] }, { "id": "PMID-10352258_T8", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 912, 921 ] ], "normalized": [] }, { "id": "PMID-10352258_T9", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1220, 1224 ] ], "normalized": [] } ]

[ { "id": "PMID-10352258_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 398, 407 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352258_T1" }, { "role": "Cause", "ref_id": "PMID-10352258_E3" } ] }, { "id": "PMID-10352258_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 398, 407 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352258_T2" }, { "role": "Cause", "ref_id": "PMID-10352258_E3" } ] }, { "id": "PMID-10352258_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 443, 453 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352258_T3" } ] }, { "id": "PMID-10352258_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 509, 519 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352258_T3" } ] }, { "id": "PMID-10352258_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 729, 739 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352258_T5" } ] }, { "id": "PMID-10352258_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 729, 739 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352258_T4" } ] }, { "id": "PMID-10352258_E7", "type": "Negative_regulation", "trigger": { "text": [ "abnormal" ], "offsets": [ [ 832, 840 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352258_E9" } ] }, { "id": "PMID-10352258_E8", "type": "Negative_regulation", "trigger": { "text": [ "abnormal" ], "offsets": [ [ 832, 840 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352258_E10" } ] }, { "id": "PMID-10352258_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 841, 851 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352258_T4" } ] }, { "id": "PMID-10352258_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 841, 851 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352258_T5" } ] }, { "id": "PMID-10352258_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 881, 891 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352258_T7" } ] }, { "id": "PMID-10352258_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 881, 891 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352258_T6" } ] }, { "id": "PMID-10352258_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 881, 891 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352258_T8" } ] }, { "id": "PMID-10352258_E14", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 935, 944 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352258_E12" } ] }, { "id": "PMID-10352258_E15", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 935, 944 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352258_E11" } ] } ]

[]

[]

[ { "id": "PMID-10352279__text", "type": "abstract", "text": [ "CD28 costimulation augments IL-2 secretion of activated lamina propria T cells by increasing mRNA stability without enhancing IL-2 gene transactivation. \nThe pathways leading to activation in lamina propria (LP) T cells are different from peripheral T cells. LP T cells exhibit enhanced IL-2 secretion when activated through the CD2 pathway. Coligation of CD28 leads to synergistic enhancement of IL-2 secretion. Previous studies have characterized the CD28 augmentation of TCR-mediated signaling in peripheral blood T cells through transcriptional activation of an IL-2 promoter CD28 response element (CD28RE), along with enhanced mRNA stability. This study characterized molecular events involved in CD28 costimulation of IL-2 production in LP mononuclear cells (LPMC). LPMC exhibited increased IL-2 production in response to CD28 costimulation, compared with cells activated through CD2 alone. IL-2 secretion was paralleled by increased expression of IL-2 mRNA, resulting from enhanced IL-2 mRNA stability. In contrast to transcriptional activation in PBMC, EMSA revealed that CD28 coligation of CD2-activated LPMC does not result in increased binding of trans-factors to the CD28RE, nor did Western blots detect changes in I-kappaBalpha or I-kappaBbeta levels following CD28 coligation. Furthermore, CD28 coligation fails to enhance IL-2 promoter-reporter or RE/AP construct expression in CD2-activated LPMC. The results reported herein indicate that the molecular mechanisms involved in CD28 cosignaling and regulation of IL-2 secretion in LP T cells are unique to that compartment and differ from those seen in peripheral blood T cells. These observations suggest a biological significance for different mechanisms of IL-2 activation in initiation and maintenance of the cytokine repertoire found in the mucosa. " ], "offsets": [ [ 0, 1818 ] ] } ]

[ { "id": "PMID-10352279_T1", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-10352279_T2", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 28, 32 ] ], "normalized": [] }, { "id": "PMID-10352279_T3", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 126, 130 ] ], "normalized": [] }, { "id": "PMID-10352279_T4", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 287, 291 ] ], "normalized": [] }, { "id": "PMID-10352279_T5", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 356, 360 ] ], "normalized": [] }, { "id": "PMID-10352279_T6", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 397, 401 ] ], "normalized": [] }, { "id": "PMID-10352279_T7", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 453, 457 ] ], "normalized": [] }, { "id": "PMID-10352279_T8", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 566, 570 ] ], "normalized": [] }, { "id": "PMID-10352279_T9", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 580, 584 ] ], "normalized": [] }, { "id": "PMID-10352279_T10", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 702, 706 ] ], "normalized": [] }, { "id": "PMID-10352279_T11", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 724, 728 ] ], "normalized": [] }, { "id": "PMID-10352279_T12", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 797, 801 ] ], "normalized": [] }, { "id": "PMID-10352279_T13", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 828, 832 ] ], "normalized": [] }, { "id": "PMID-10352279_T14", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 897, 901 ] ], "normalized": [] }, { "id": "PMID-10352279_T15", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 954, 958 ] ], "normalized": [] }, { "id": "PMID-10352279_T16", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 989, 993 ] ], "normalized": [] }, { "id": "PMID-10352279_T17", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 1080, 1084 ] ], "normalized": [] }, { "id": "PMID-10352279_T18", "type": "Protein", "text": [ "I-kappaBalpha" ], "offsets": [ [ 1227, 1240 ] ], "normalized": [] }, { "id": "PMID-10352279_T19", "type": "Protein", "text": [ "I-kappaBbeta" ], "offsets": [ [ 1244, 1256 ] ], "normalized": [] }, { "id": "PMID-10352279_T20", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 1274, 1278 ] ], "normalized": [] }, { "id": "PMID-10352279_T21", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 1304, 1308 ] ], "normalized": [] }, { "id": "PMID-10352279_T22", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1337, 1341 ] ], "normalized": [] }, { "id": "PMID-10352279_T23", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 1492, 1496 ] ], "normalized": [] }, { "id": "PMID-10352279_T24", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1527, 1531 ] ], "normalized": [] }, { "id": "PMID-10352279_T25", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1724, 1728 ] ], "normalized": [] } ]

[ { "id": "PMID-10352279_E1", "type": "Positive_regulation", "trigger": { "text": [ "costimulation" ], "offsets": [ [ 5, 18 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T1" } ] }, { "id": "PMID-10352279_E2", "type": "Positive_regulation", "trigger": { "text": [ "augments" ], "offsets": [ [ 19, 27 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_E3" }, { "role": "Cause", "ref_id": "PMID-10352279_E4" } ] }, { "id": "PMID-10352279_E3", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 33, 42 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T2" } ] }, { "id": "PMID-10352279_E4", "type": "Positive_regulation", "trigger": { "text": [ "increasing" ], "offsets": [ [ 82, 92 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T3" }, { "role": "Cause", "ref_id": "PMID-10352279_E1" } ] }, { "id": "PMID-10352279_E5", "type": "Positive_regulation", "trigger": { "text": [ "enhancing" ], "offsets": [ [ 116, 125 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_E6" }, { "role": "Cause", "ref_id": "PMID-10352279_E1" } ] }, { "id": "PMID-10352279_E6", "type": "Positive_regulation", "trigger": { "text": [ "transactivation" ], "offsets": [ [ 136, 151 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T3" } ] }, { "id": "PMID-10352279_E7", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 278, 286 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_E8" } ] }, { "id": "PMID-10352279_E8", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 292, 301 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T4" } ] }, { "id": "PMID-10352279_E9", "type": "Binding", "trigger": { "text": [ "Coligation" ], "offsets": [ [ 342, 352 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T5" } ] }, { "id": "PMID-10352279_E10", "type": "Positive_regulation", "trigger": { "text": [ "leads to synergistic enhancement" ], "offsets": [ [ 361, 393 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_E11" }, { "role": "Cause", "ref_id": "PMID-10352279_E9" } ] }, { "id": "PMID-10352279_E11", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 402, 411 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T6" } ] }, { "id": "PMID-10352279_E12", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 623, 631 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T8" } ] }, { "id": "PMID-10352279_E13", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 690, 698 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_E14" } ] }, { "id": "PMID-10352279_E14", "type": "Positive_regulation", "trigger": { "text": [ "costimulation" ], "offsets": [ [ 707, 720 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_E15" }, { "role": "Cause", "ref_id": "PMID-10352279_T10" } ] }, { "id": "PMID-10352279_E15", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 729, 739 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T11" } ] }, { "id": "PMID-10352279_E16", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 802, 812 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T12" } ] }, { "id": "PMID-10352279_E17", "type": "Positive_regulation", "trigger": { "text": [ "in response to" ], "offsets": [ [ 813, 827 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_E16" } ] }, { "id": "PMID-10352279_E18", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 902, 911 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T14" } ] }, { "id": "PMID-10352279_E19", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 930, 939 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_E20" } ] }, { "id": "PMID-10352279_E20", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 940, 950 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T15" } ] }, { "id": "PMID-10352279_E21", "type": "Positive_regulation", "trigger": { "text": [ "resulting" ], "offsets": [ [ 965, 974 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_E19" }, { "role": "Cause", "ref_id": "PMID-10352279_E22" } ] }, { "id": "PMID-10352279_E22", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 980, 988 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T16" } ] }, { "id": "PMID-10352279_E23", "type": "Binding", "trigger": { "text": [ "coligation" ], "offsets": [ [ 1085, 1095 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T17" } ] }, { "id": "PMID-10352279_E24", "type": "Regulation", "trigger": { "text": [ "changes" ], "offsets": [ [ 1216, 1223 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_E27" }, { "role": "Cause", "ref_id": "PMID-10352279_E28" } ] }, { "id": "PMID-10352279_E25", "type": "Regulation", "trigger": { "text": [ "changes" ], "offsets": [ [ 1216, 1223 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_E26" }, { "role": "Cause", "ref_id": "PMID-10352279_E28" } ] }, { "id": "PMID-10352279_E26", "type": "Gene_expression", "trigger": { "text": [ "levels" ], "offsets": [ [ 1257, 1263 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T18" } ] }, { "id": "PMID-10352279_E27", "type": "Gene_expression", "trigger": { "text": [ "levels" ], "offsets": [ [ 1257, 1263 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T19" } ] }, { "id": "PMID-10352279_E28", "type": "Binding", "trigger": { "text": [ "coligation" ], "offsets": [ [ 1279, 1289 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T20" } ] }, { "id": "PMID-10352279_E29", "type": "Binding", "trigger": { "text": [ "coligation" ], "offsets": [ [ 1309, 1319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T21" } ] }, { "id": "PMID-10352279_E30", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 1480, 1488 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_E31" } ] }, { "id": "PMID-10352279_E31", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1513, 1523 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_E32" } ] }, { "id": "PMID-10352279_E32", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 1532, 1541 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10352279_T24" } ] } ]

[]

[]

[ { "id": "PMID-10357820__text", "type": "abstract", "text": [ "Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes. \nHere we show that the lymphoid lineage-determining factors Ikaros and Aiolos can function as strong transcriptional repressors. This function is mediated through two repression domains and is dependent upon the promoter context and cell type. Repression by Ikaros proteins correlates with hypo-acetylation of core histones at promoter sites and is relieved by histone deacetylase inhibitors. Consistent with these findings, Ikaros and its repression domains can interact in vivo and in vitro with the mSin3 family of co-repressors which bind to histone deacetylases. Based on these and our recent findings of associations between Ikaros and Mi-2-HDAC, we propose that Ikaros family members modulate gene expression during lymphocyte development by recruiting distinct histone deacetylase complexes to specific promoters. " ], "offsets": [ [ 0, 905 ] ] } ]

[ { "id": "PMID-10357820_T1", "type": "Protein", "text": [ "Ikaros" ], "offsets": [ [ 14, 20 ] ], "normalized": [] }, { "id": "PMID-10357820_T2", "type": "Protein", "text": [ "Aiolos" ], "offsets": [ [ 25, 31 ] ], "normalized": [] }, { "id": "PMID-10357820_T3", "type": "Protein", "text": [ "Ikaros" ], "offsets": [ [ 143, 149 ] ], "normalized": [] }, { "id": "PMID-10357820_T4", "type": "Protein", "text": [ "Aiolos" ], "offsets": [ [ 154, 160 ] ], "normalized": [] }, { "id": "PMID-10357820_T5", "type": "Protein", "text": [ "Ikaros" ], "offsets": [ [ 341, 347 ] ], "normalized": [] }, { "id": "PMID-10357820_T6", "type": "Protein", "text": [ "Ikaros" ], "offsets": [ [ 508, 514 ] ], "normalized": [] }, { "id": "PMID-10357820_T7", "type": "Protein", "text": [ "Ikaros" ], "offsets": [ [ 714, 720 ] ], "normalized": [] }, { "id": "PMID-10357820_T8", "type": "Protein", "text": [ "Mi-2-HDAC" ], "offsets": [ [ 725, 734 ] ], "normalized": [] }, { "id": "PMID-10357820_T9", "type": "Protein", "text": [ "Ikaros" ], "offsets": [ [ 752, 758 ] ], "normalized": [] } ]

[ { "id": "PMID-10357820_E1", "type": "Binding", "trigger": { "text": [ "interact" ], "offsets": [ [ 546, 554 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10357820_T6" } ] }, { "id": "PMID-10357820_E2", "type": "Binding", "trigger": { "text": [ "associations" ], "offsets": [ [ 693, 705 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10357820_T7" }, { "role": "Theme", "ref_id": "PMID-10357820_T8" } ] } ]

[]

[]

[ { "id": "PMID-10358154__text", "type": "abstract", "text": [ "New immunosuppressive drug PNU156804 blocks IL-2-dependent proliferation and NF-kappa B and AP-1 activation. \nWe had previously shown that the drug undecylprodigiosin (UP) blocks human lymphocyte proliferation in vitro. We have now investigated the mechanism of action of a new analogue of UP, PNU156804, which shows a more favorable activity profile than UP in mice. We demonstrate here that the biological effect of PNU156804 in vitro is indistinguishable from UP: PNU156804 blocks human T cell proliferation in mid-late G1, as determined by cell cycle analysis, expression of cyclins, and cyclin-dependent kinases and retinoblastoma phosphorylation. In addition, we show that PNU156804 does not block significantly the induction of either IL-2 or IL-2R alpha- and gamma-chains but inhibits IL-2-dependent T cell proliferation. We have investigated several molecular pathways that are known to be activated by IL-2 in T cells. We show that PNU156804 does not inhibit c-myc and bcl-2 mRNA induction. On the other hand, PNU156804 efficiently inhibits the activation of the NF-kappa B and AP-1 transcription factors. PNU156804 inhibition of NF-kappa B activation is due to the inhibition of the degradation of I kappa B-alpha and I kappa B-beta. PNU156804 action is restricted to some signaling pathways; it does not affect NF-kappa B activation by PMA in T cells but blocks that induced by CD40 cross-linking in B lymphocytes. We conclude that the prodigiosin family of immunosuppressants is a new family of molecules that show a novel target specificity clearly distinct from that of other immunosuppressive drugs such as cyclosporin A, FK506, and rapamycin. " ], "offsets": [ [ 0, 1660 ] ] } ]

[ { "id": "PMID-10358154_T1", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 44, 48 ] ], "normalized": [] }, { "id": "PMID-10358154_T2", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 742, 746 ] ], "normalized": [] }, { "id": "PMID-10358154_T3", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 793, 797 ] ], "normalized": [] }, { "id": "PMID-10358154_T4", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 912, 916 ] ], "normalized": [] }, { "id": "PMID-10358154_T5", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 969, 974 ] ], "normalized": [] }, { "id": "PMID-10358154_T6", "type": "Protein", "text": [ "bcl-2" ], "offsets": [ [ 979, 984 ] ], "normalized": [] }, { "id": "PMID-10358154_T7", "type": "Protein", "text": [ "I kappa B-alpha" ], "offsets": [ [ 1209, 1224 ] ], "normalized": [] }, { "id": "PMID-10358154_T8", "type": "Protein", "text": [ "I kappa B-beta" ], "offsets": [ [ 1229, 1243 ] ], "normalized": [] }, { "id": "PMID-10358154_T9", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 1390, 1394 ] ], "normalized": [] } ]

[ { "id": "PMID-10358154_E1", "type": "Negative_regulation", "trigger": { "text": [ "block" ], "offsets": [ [ 698, 703 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358154_E2" } ] }, { "id": "PMID-10358154_E2", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 722, 731 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358154_T2" } ] }, { "id": "PMID-10358154_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 961, 968 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358154_E6" } ] }, { "id": "PMID-10358154_E4", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 961, 968 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358154_E5" } ] }, { "id": "PMID-10358154_E5", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 990, 999 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358154_T5" } ] }, { "id": "PMID-10358154_E6", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 990, 999 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358154_T6" } ] }, { "id": "PMID-10358154_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1176, 1186 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358154_E9" } ] }, { "id": "PMID-10358154_E8", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1176, 1186 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358154_E10" } ] }, { "id": "PMID-10358154_E9", "type": "Protein_catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1194, 1205 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358154_T8" } ] }, { "id": "PMID-10358154_E10", "type": "Protein_catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1194, 1205 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358154_T7" } ] }, { "id": "PMID-10358154_E11", "type": "Binding", "trigger": { "text": [ "cross-linking" ], "offsets": [ [ 1395, 1408 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358154_T9" } ] } ]

[]

[]

[ { "id": "PMID-10358173__text", "type": "abstract", "text": [ "IL-12 induces IFN regulating factor-1 (IRF-1) gene expression in human NK and T cells. \nIL-12 is a critical immunoregulatory cytokine that promotes cell-mediated immune responses and the differentiation of naive CD4+ cells to Th1 cells; however, relatively few IL-12 target genes have been identified. To better clarify the molecular basis of IL-12 action, we set out to characterize genes up-regulated by IL-12, first by contrasting IL-12- and IFN-alpha-inducible genes. We identified several genes up-regulated by IL-12, namely, MIP-1alpha, MIP-1beta, IL-1RA, and IFN regulatory factor-1 (IRF-1). IRF-1 is a transcription factor regulated by IFNs that is also essential for Th1 responses. We demonstrated that IL-12 directly up-regulates IRF-1 to the same extent as IFN-alpha in normal human T cells and in NK cells. We showed that IL-12 had a direct effect on IRF-1, an effect not mediated indirectly by the induction of IFN-gamma production. Furthermore, IL-2 and IL-12 synergistically induced IRF-1, whereas IFN-alpha and IL-12 did not. The participation of STAT4 in the regulation of IRF-1 was demonstrated in two ways. First, STAT4 was required for the IL-12-dependent transactivation of an IRF-1 reporter construct, and second, STAT4 binding to the IRF-1 promoter was shown using EMSA. In contrast to IL-12, no up-regulation of IRF-1 was found in IL-4-stimulated cells, and IL-4 did not block IL-12-dependent up-regulation of IRF-1. Therefore, IRF-1 may be an important contributor to IL-12 signaling, and we speculate that the defective IL-12 responses seen in IRF-1-/- mice might be attributable, in part, to the absence of this transcription factor. " ], "offsets": [ [ 0, 1661 ] ] } ]

[ { "id": "PMID-10358173_T1", "type": "Protein", "text": [ "IFN regulating factor-1" ], "offsets": [ [ 14, 37 ] ], "normalized": [] }, { "id": "PMID-10358173_T2", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 39, 44 ] ], "normalized": [] }, { "id": "PMID-10358173_T3", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 212, 215 ] ], "normalized": [] }, { "id": "PMID-10358173_T4", "type": "Protein", "text": [ "MIP-1alpha" ], "offsets": [ [ 531, 541 ] ], "normalized": [] }, { "id": "PMID-10358173_T5", "type": "Protein", "text": [ "MIP-1beta" ], "offsets": [ [ 543, 552 ] ], "normalized": [] }, { "id": "PMID-10358173_T6", "type": "Protein", "text": [ "IL-1RA" ], "offsets": [ [ 554, 560 ] ], "normalized": [] }, { "id": "PMID-10358173_T7", "type": "Protein", "text": [ "IFN regulatory factor-1" ], "offsets": [ [ 566, 589 ] ], "normalized": [] }, { "id": "PMID-10358173_T8", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 591, 596 ] ], "normalized": [] }, { "id": "PMID-10358173_T9", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 599, 604 ] ], "normalized": [] }, { "id": "PMID-10358173_T10", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 740, 745 ] ], "normalized": [] }, { "id": "PMID-10358173_T11", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 863, 868 ] ], "normalized": [] }, { "id": "PMID-10358173_T12", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 924, 933 ] ], "normalized": [] }, { "id": "PMID-10358173_T13", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 998, 1003 ] ], "normalized": [] }, { "id": "PMID-10358173_T14", "type": "Protein", "text": [ "STAT4" ], "offsets": [ [ 1063, 1068 ] ], "normalized": [] }, { "id": "PMID-10358173_T15", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 1090, 1095 ] ], "normalized": [] }, { "id": "PMID-10358173_T16", "type": "Protein", "text": [ "STAT4" ], "offsets": [ [ 1133, 1138 ] ], "normalized": [] }, { "id": "PMID-10358173_T17", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 1198, 1203 ] ], "normalized": [] }, { "id": "PMID-10358173_T18", "type": "Protein", "text": [ "STAT4" ], "offsets": [ [ 1236, 1241 ] ], "normalized": [] }, { "id": "PMID-10358173_T19", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 1257, 1262 ] ], "normalized": [] }, { "id": "PMID-10358173_T20", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 1336, 1341 ] ], "normalized": [] }, { "id": "PMID-10358173_T21", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1355, 1359 ] ], "normalized": [] }, { "id": "PMID-10358173_T22", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1382, 1386 ] ], "normalized": [] }, { "id": "PMID-10358173_T23", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 1434, 1439 ] ], "normalized": [] }, { "id": "PMID-10358173_T24", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 1452, 1457 ] ], "normalized": [] }, { "id": "PMID-10358173_T25", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 1570, 1575 ] ], "normalized": [] }, { "id": "PMID-10358173_T39", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1263, 1271 ] ], "normalized": [] } ]

[ { "id": "PMID-10358173_E1", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 6, 13 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_E2" } ] }, { "id": "PMID-10358173_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 51, 61 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_T2" } ] }, { "id": "PMID-10358173_E3", "type": "Positive_regulation", "trigger": { "text": [ "up-regulated" ], "offsets": [ [ 500, 512 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_T8" } ] }, { "id": "PMID-10358173_E4", "type": "Positive_regulation", "trigger": { "text": [ "up-regulated" ], "offsets": [ [ 500, 512 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_T5" } ] }, { "id": "PMID-10358173_E5", "type": "Positive_regulation", "trigger": { "text": [ "up-regulated" ], "offsets": [ [ 500, 512 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_T6" } ] }, { "id": "PMID-10358173_E6", "type": "Positive_regulation", "trigger": { "text": [ "up-regulated" ], "offsets": [ [ 500, 512 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_T4" } ] }, { "id": "PMID-10358173_E7", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 631, 640 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_T9" } ] }, { "id": "PMID-10358173_E8", "type": "Positive_regulation", "trigger": { "text": [ "up-regulates" ], "offsets": [ [ 727, 739 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_T10" } ] }, { "id": "PMID-10358173_E9", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 853, 859 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_T11" } ] }, { "id": "PMID-10358173_E10", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 884, 892 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_E9" }, { "role": "Cause", "ref_id": "PMID-10358173_E11" } ] }, { "id": "PMID-10358173_E11", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 911, 920 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_E12" } ] }, { "id": "PMID-10358173_E12", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 934, 944 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_T12" } ] }, { "id": "PMID-10358173_E13", "type": "Positive_regulation", "trigger": { "text": [ "synergistically induced" ], "offsets": [ [ 974, 997 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_T13" } ] }, { "id": "PMID-10358173_E14", "type": "Regulation", "trigger": { "text": [ "participation" ], "offsets": [ [ 1046, 1059 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_E15" }, { "role": "Cause", "ref_id": "PMID-10358173_T14" } ] }, { "id": "PMID-10358173_E15", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1076, 1086 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_T15" } ] }, { "id": "PMID-10358173_E16", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1242, 1249 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_T18" }, { "role": "Theme", "ref_id": "PMID-10358173_T19" }, { "role": "Site", "ref_id": "PMID-10358173_T39" } ] }, { "id": "PMID-10358173_E17", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 1319, 1332 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_T20" } ] }, { "id": "PMID-10358173_E18", "type": "Negative_regulation", "trigger": { "text": [ "block" ], "offsets": [ [ 1395, 1400 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_E19" }, { "role": "Cause", "ref_id": "PMID-10358173_T22" } ] }, { "id": "PMID-10358173_E19", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 1417, 1430 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_T23" } ] }, { "id": "PMID-10358173_E20", "type": "Positive_regulation", "trigger": { "text": [ "absence" ], "offsets": [ [ 1623, 1630 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10358173_T24" } ] } ]

[ { "id": "PMID-10358173_1", "entity_ids": [ "PMID-10358173_T2", "PMID-10358173_T1" ] }, { "id": "PMID-10358173_2", "entity_ids": [ "PMID-10358173_T8", "PMID-10358173_T7" ] } ]

[]

[ { "id": "PMID-10358756__text", "type": "abstract", "text": [ "Transcriptional regulation of T lymphocyte development and function. \nThe development and function of T lymphocytes are regulated tightly by signal transduction pathways that include specific cell-surface receptors, intracellular signaling molecules, and nuclear transcription factors. Since 1988, several families of functionally important T cell transcription factors have been identified. These include the Ikaros, LKLF, and GATA3 zinc-finger proteins; the Ets, CREB/ATF, and NF-kappa B/Rel/NFAT transcription factors; the Stat proteins; and HMG box transcription factors such as LEF1, TCF1, and Sox4. In this review, we summarize our current understanding of the transcriptional regulation of T cell development and function with particular emphasis on the results of recent gene targeting and transgenic experiments. In addition to increasing our understanding of the molecular pathways that regulate T cell development and function, these results have suggested novel targets for genetic and pharmacological manipulation of T cell immunity. " ], "offsets": [ [ 0, 1047 ] ] } ]

[ { "id": "PMID-10358756_T1", "type": "Protein", "text": [ "Ikaros" ], "offsets": [ [ 410, 416 ] ], "normalized": [] }, { "id": "PMID-10358756_T2", "type": "Protein", "text": [ "LKLF" ], "offsets": [ [ 418, 422 ] ], "normalized": [] }, { "id": "PMID-10358756_T3", "type": "Protein", "text": [ "GATA3" ], "offsets": [ [ 428, 433 ] ], "normalized": [] }, { "id": "PMID-10358756_T4", "type": "Protein", "text": [ "CREB" ], "offsets": [ [ 465, 469 ] ], "normalized": [] }, { "id": "PMID-10358756_T5", "type": "Protein", "text": [ "ATF" ], "offsets": [ [ 470, 473 ] ], "normalized": [] }, { "id": "PMID-10358756_T6", "type": "Protein", "text": [ "LEF1" ], "offsets": [ [ 583, 587 ] ], "normalized": [] }, { "id": "PMID-10358756_T7", "type": "Protein", "text": [ "TCF1" ], "offsets": [ [ 589, 593 ] ], "normalized": [] }, { "id": "PMID-10358756_T8", "type": "Protein", "text": [ "Sox4" ], "offsets": [ [ 599, 603 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-10358756_1", "entity_ids": [ "PMID-10358756_T4", "PMID-10358756_T5" ] } ]

[]

[ { "id": "PMID-10359895__text", "type": "abstract", "text": [ "Binding of YY1 and Oct1 to a novel element that downregulates expression of IL-5 in human T cells. \nBACKGROUND: IL-5 controls development of eosinophilia and has been shown to be involved in the pathogenesis of allergic diseases. In both atopic and nonatopic asthma, elevated IL-5 has been detected in peripheral blood and the airways. IL-5 is produced mainly by activated T cells, and its expression is regulated at the transcriptional level. OBJECTIVE: This study focuses on the functional analysis of the human IL-5 (hIL-5) promoter and characterization of cis -regulatory elements and transcription factors involved in the suppression of IL-5 transcription in T cells. METHODS: Methods used in this study include DNase I footprint assays, electrophoretic mobility shift assays, and functional analysis by mammalian cell transfection involving deletion analysis and site-directed mutagenesis. RESULTS: We identified 5 protein binding regions (BRs) located within the proximal hIL-5 promoter. Functional analysis indicates that the BRs are involved in control of hIL-5 promoter activity. Two of these regions, BR3 and BR4 located at positions -102 to -73, have not previously been described as regulators of IL-5 expression in T cells. We show that the BR3 sequence contains a novel negative regulatory element located at positions -90 to -79 of the hIL-5 promoter, which binds Oct1, octamer-like, and YY1 nuclear factors. Substitution mutations, which abolished binding of these proteins to the BR3 sequence, significantly increased hIL-5 promoter activity in activated T cells. CONCLUSION: We suggest that Oct1, YY1, and octamer-like factors binding to the -90/-79 sequence within the proximal IL-5 promoter are involved in suppression of IL-5 transcription in T cells. " ], "offsets": [ [ 0, 1774 ] ] } ]

[ { "id": "PMID-10359895_T1", "type": "Protein", "text": [ "YY1" ], "offsets": [ [ 11, 14 ] ], "normalized": [] }, { "id": "PMID-10359895_T2", "type": "Protein", "text": [ "Oct1" ], "offsets": [ [ 19, 23 ] ], "normalized": [] }, { "id": "PMID-10359895_T3", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 76, 80 ] ], "normalized": [] }, { "id": "PMID-10359895_T4", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 112, 116 ] ], "normalized": [] }, { "id": "PMID-10359895_T5", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 276, 280 ] ], "normalized": [] }, { "id": "PMID-10359895_T6", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 336, 340 ] ], "normalized": [] }, { "id": "PMID-10359895_T7", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 514, 518 ] ], "normalized": [] }, { "id": "PMID-10359895_T8", "type": "Protein", "text": [ "hIL-5" ], "offsets": [ [ 520, 525 ] ], "normalized": [] }, { "id": "PMID-10359895_T9", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 642, 646 ] ], "normalized": [] }, { "id": "PMID-10359895_T10", "type": "Protein", "text": [ "hIL-5" ], "offsets": [ [ 979, 984 ] ], "normalized": [] }, { "id": "PMID-10359895_T11", "type": "Protein", "text": [ "hIL-5" ], "offsets": [ [ 1065, 1070 ] ], "normalized": [] }, { "id": "PMID-10359895_T12", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 1210, 1214 ] ], "normalized": [] }, { "id": "PMID-10359895_T13", "type": "Protein", "text": [ "hIL-5" ], "offsets": [ [ 1352, 1357 ] ], "normalized": [] }, { "id": "PMID-10359895_T14", "type": "Protein", "text": [ "Oct1" ], "offsets": [ [ 1380, 1384 ] ], "normalized": [] }, { "id": "PMID-10359895_T15", "type": "Protein", "text": [ "YY1" ], "offsets": [ [ 1404, 1407 ] ], "normalized": [] }, { "id": "PMID-10359895_T16", "type": "Protein", "text": [ "hIL-5" ], "offsets": [ [ 1536, 1541 ] ], "normalized": [] }, { "id": "PMID-10359895_T17", "type": "Protein", "text": [ "Oct1" ], "offsets": [ [ 1610, 1614 ] ], "normalized": [] }, { "id": "PMID-10359895_T18", "type": "Protein", "text": [ "YY1" ], "offsets": [ [ 1616, 1619 ] ], "normalized": [] }, { "id": "PMID-10359895_T19", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 1698, 1702 ] ], "normalized": [] }, { "id": "PMID-10359895_T20", "type": "Protein", "text": [ "IL-5" ], "offsets": [ [ 1743, 1747 ] ], "normalized": [] }, { "id": "PMID-10359895_T31", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1071, 1079 ] ], "normalized": [] }, { "id": "PMID-10359895_T35", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1358, 1366 ] ], "normalized": [] }, { "id": "PMID-10359895_T40", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1542, 1550 ] ], "normalized": [] }, { "id": "PMID-10359895_T42", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1703, 1711 ] ], "normalized": [] } ]

[ { "id": "PMID-10359895_E1", "type": "Binding", "trigger": { "text": [ "Binding" ], "offsets": [ [ 0, 7 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T2" } ] }, { "id": "PMID-10359895_E2", "type": "Binding", "trigger": { "text": [ "Binding" ], "offsets": [ [ 0, 7 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T1" } ] }, { "id": "PMID-10359895_E3", "type": "Negative_regulation", "trigger": { "text": [ "downregulates" ], "offsets": [ [ 48, 61 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_E4" } ] }, { "id": "PMID-10359895_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 62, 72 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T3" } ] }, { "id": "PMID-10359895_E5", "type": "Positive_regulation", "trigger": { "text": [ "elevated" ], "offsets": [ [ 267, 275 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T5" } ] }, { "id": "PMID-10359895_E6", "type": "Gene_expression", "trigger": { "text": [ "produced" ], "offsets": [ [ 344, 352 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T6" } ] }, { "id": "PMID-10359895_E7", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 404, 413 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_E6" } ] }, { "id": "PMID-10359895_E8", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 611, 619 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_E9" } ] }, { "id": "PMID-10359895_E9", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 627, 638 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_E10" } ] }, { "id": "PMID-10359895_E10", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 647, 660 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T9" } ] }, { "id": "PMID-10359895_E11", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 1054, 1061 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T11" }, { "role": "Site", "ref_id": "PMID-10359895_T31" } ] }, { "id": "PMID-10359895_E12", "type": "Regulation", "trigger": { "text": [ "regulators" ], "offsets": [ [ 1196, 1206 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_E13" } ] }, { "id": "PMID-10359895_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1215, 1225 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T12" } ] }, { "id": "PMID-10359895_E14", "type": "Negative_regulation", "trigger": { "text": [ "negative regulatory" ], "offsets": [ [ 1285, 1304 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T13" }, { "role": "Site", "ref_id": "PMID-10359895_T35" } ] }, { "id": "PMID-10359895_E15", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 1374, 1379 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T14" } ] }, { "id": "PMID-10359895_E16", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 1374, 1379 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T15" } ] }, { "id": "PMID-10359895_E17", "type": "Negative_regulation", "trigger": { "text": [ "abolished" ], "offsets": [ [ 1455, 1464 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_E20" } ] }, { "id": "PMID-10359895_E18", "type": "Negative_regulation", "trigger": { "text": [ "abolished" ], "offsets": [ [ 1455, 1464 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_E19" } ] }, { "id": "PMID-10359895_E19", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1465, 1472 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T14" } ] }, { "id": "PMID-10359895_E20", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1465, 1472 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T15" } ] }, { "id": "PMID-10359895_E21", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1526, 1535 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T16" }, { "role": "Site", "ref_id": "PMID-10359895_T40" } ] }, { "id": "PMID-10359895_E22", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1646, 1653 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T18" }, { "role": "Theme", "ref_id": "PMID-10359895_T19" }, { "role": "Site", "ref_id": "PMID-10359895_T42" } ] }, { "id": "PMID-10359895_E23", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1646, 1653 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T17" }, { "role": "Theme", "ref_id": "PMID-10359895_T19" }, { "role": "Site", "ref_id": "PMID-10359895_T42" } ] }, { "id": "PMID-10359895_E24", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1646, 1653 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T19" }, { "role": "Site", "ref_id": "PMID-10359895_T42" } ] }, { "id": "PMID-10359895_E25", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 1716, 1724 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_E28" }, { "role": "Cause", "ref_id": "PMID-10359895_E23" } ] }, { "id": "PMID-10359895_E26", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 1716, 1724 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_E28" }, { "role": "Cause", "ref_id": "PMID-10359895_E24" } ] }, { "id": "PMID-10359895_E27", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 1716, 1724 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_E28" }, { "role": "Cause", "ref_id": "PMID-10359895_E22" } ] }, { "id": "PMID-10359895_E28", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 1728, 1739 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_E29" } ] }, { "id": "PMID-10359895_E29", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1748, 1761 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10359895_T20" } ] } ]

[ { "id": "PMID-10359895_1", "entity_ids": [ "PMID-10359895_T7", "PMID-10359895_T8" ] } ]

[]

[ { "id": "PMID-10364157__text", "type": "abstract", "text": [ "Direct interaction of hematopoietic transcription factors PU.1 and GATA-1: functional antagonism in erythroid cells. \nMalignant transformation usually inhibits terminal cell differentiation but the precise mechanisms involved are not understood. PU.1 is a hematopoietic-specific Ets family transcription factor that is required for development of some lymphoid and myeloid lineages. PU.1 can also act as an oncoprotein as activation of its expression in erythroid precursors by proviral insertion or transgenesis causes erythroleukemias in mice. Restoration of terminal differentiation in the mouse erythroleukemia (MEL) cells requires a decline in the level of PU.1, indicating that PU.1 can block erythroid differentiation. Here we investigate the mechanism by which PU.1 interferes with erythroid differentiation. We find that PU.1 interacts directly with GATA-1, a zinc finger transcription factor required for erythroid differentiation. Interaction between PU.1 and GATA-1 requires intact DNA-binding domains in both proteins. PU.1 represses GATA-1-mediated transcriptional activation. Both the DNA binding and transactivation domains of PU.1 are required for repression and both domains are also needed to block terminal differentiation in MEL cells. We also show that ectopic expression of PU.1 in Xenopus embryos is sufficient to block erythropoiesis during normal development. Furthermore, introduction of exogenous GATA-1 in both MEL cells and Xenopus embryos and explants relieves the block to erythroid differentiation imposed by PU.1. Our results indicate that the stoichiometry of directly interacting but opposing transcription factors may be a crucial determinant governing processes of normal differentiation and malignant transformation. " ], "offsets": [ [ 0, 1756 ] ] } ]

[ { "id": "PMID-10364157_T1", "type": "Protein", "text": [ "PU.1" ], "offsets": [ [ 58, 62 ] ], "normalized": [] }, { "id": "PMID-10364157_T2", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 67, 73 ] ], "normalized": [] }, { "id": "PMID-10364157_T3", "type": "Protein", "text": [ "PU.1" ], "offsets": [ [ 246, 250 ] ], "normalized": [] }, { "id": "PMID-10364157_T4", "type": "Protein", "text": [ "PU.1" ], "offsets": [ [ 383, 387 ] ], "normalized": [] }, { "id": "PMID-10364157_T5", "type": "Protein", "text": [ "PU.1" ], "offsets": [ [ 662, 666 ] ], "normalized": [] }, { "id": "PMID-10364157_T6", "type": "Protein", "text": [ "PU.1" ], "offsets": [ [ 684, 688 ] ], "normalized": [] }, { "id": "PMID-10364157_T7", "type": "Protein", "text": [ "PU.1" ], "offsets": [ [ 769, 773 ] ], "normalized": [] }, { "id": "PMID-10364157_T8", "type": "Protein", "text": [ "PU.1" ], "offsets": [ [ 830, 834 ] ], "normalized": [] }, { "id": "PMID-10364157_T9", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 859, 865 ] ], "normalized": [] }, { "id": "PMID-10364157_T10", "type": "Protein", "text": [ "PU.1" ], "offsets": [ [ 962, 966 ] ], "normalized": [] }, { "id": "PMID-10364157_T11", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 971, 977 ] ], "normalized": [] }, { "id": "PMID-10364157_T12", "type": "Protein", "text": [ "PU.1" ], "offsets": [ [ 1032, 1036 ] ], "normalized": [] }, { "id": "PMID-10364157_T13", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 1047, 1053 ] ], "normalized": [] }, { "id": "PMID-10364157_T14", "type": "Protein", "text": [ "PU.1" ], "offsets": [ [ 1143, 1147 ] ], "normalized": [] }, { "id": "PMID-10364157_T15", "type": "Protein", "text": [ "PU.1" ], "offsets": [ [ 1297, 1301 ] ], "normalized": [] }, { "id": "PMID-10364157_T16", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 1425, 1431 ] ], "normalized": [] }, { "id": "PMID-10364157_T17", "type": "Protein", "text": [ "PU.1" ], "offsets": [ [ 1542, 1546 ] ], "normalized": [] } ]

[ { "id": "PMID-10364157_E1", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 7, 18 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364157_T1" }, { "role": "Theme", "ref_id": "PMID-10364157_T2" } ] }, { "id": "PMID-10364157_E2", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 422, 432 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364157_E3" } ] }, { "id": "PMID-10364157_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 440, 450 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364157_T4" } ] }, { "id": "PMID-10364157_E4", "type": "Negative_regulation", "trigger": { "text": [ "decline in the level" ], "offsets": [ [ 638, 658 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364157_T5" } ] }, { "id": "PMID-10364157_E5", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 835, 844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364157_T8" }, { "role": "Theme", "ref_id": "PMID-10364157_T9" } ] }, { "id": "PMID-10364157_E6", "type": "Binding", "trigger": { "text": [ "Interaction" ], "offsets": [ [ 942, 953 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364157_T10" }, { "role": "Theme", "ref_id": "PMID-10364157_T11" } ] }, { "id": "PMID-10364157_E7", "type": "Positive_regulation", "trigger": { "text": [ "requires" ], "offsets": [ [ 978, 986 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364157_E6" } ] }, { "id": "PMID-10364157_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1283, 1293 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364157_T15" } ] }, { "id": "PMID-10364157_E9", "type": "Binding", "trigger": { "text": [ "interacting" ], "offsets": [ [ 1604, 1615 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364157_T16" }, { "role": "Theme", "ref_id": "PMID-10364157_T17" } ] }, { "id": "PMID-10364157_E10", "type": "Negative_regulation", "trigger": { "text": [ "opposing" ], "offsets": [ [ 1620, 1628 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364157_T17" }, { "role": "Cause", "ref_id": "PMID-10364157_T16" } ] } ]

[]

[]

[ { "id": "PMID-10364191__text", "type": "abstract", "text": [ "Potent and stable attenuation of live-HIV-1 by gain of a proteolysis-resistant inhibitor of NF-kappaB (IkappaB-alphaS32/36A) and the implications for vaccine development. \nLive-attenuated human immunodeficiency viruses (HIVs) are candidates for Acquired Immunodeficiency Syndrome (AIDS) vaccine. Based on the simian immunodeficiency virus (SIV) model for AIDS, loss-of-function (e.g. deletion of accessory genes such as nef) has been forwarded as a primary approach for creating enfeebled, but replication-competent, HIV-1/SIV. Regrettably, recent evidence suggests that loss-of-function alone is not always sufficient to prevent the emergence of virulent mutants. New strategies that attenuate via mechanisms distinct from loss-of-function are needed for enhancing the safety phenotype of viral genome. Here, we propose gain-of-function to be used simultaneously with loss-of-function as a novel approach for attenuating HIV-1. We have constructed an HIV-1 genome carrying the cDNA of a proteolysis-resistant nuclear factor-kappaB inhibitor (IkappaB-alphaS32/36A) in the nef region. HIV-1 expressing IkappaB-alphaS32/36A down-regulates viral expression and is highly attenuated in both Jurkat and peripheral blood mononuclear cells. We provide formal proof that the phenotypic and attenuating characteristics of IkappaB-alphaS32/36A permit its stable maintenance in a live, replicating HIV-1 despite 180 days of forced ex vivo passaging in tissue culture. As compared with other open-reading frames embedded into HIV/SIV genome, this degree of stability is unprecedented. Thus, IkappaB-alphaS32/36A offers proof-of-principle that artifactually gained functions, when used to attenuate the replication of live HIV-1, can be stable. These findings illustrate gain-of-function as a feasible strategy for developing safer live-attenuated HIVs to be tested as candidates for AIDS vaccine. " ], "offsets": [ [ 0, 1885 ] ] } ]

[ { "id": "PMID-10364191_T1", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 103, 116 ] ], "normalized": [] }, { "id": "PMID-10364191_T2", "type": "Protein", "text": [ "nef" ], "offsets": [ [ 420, 423 ] ], "normalized": [] }, { "id": "PMID-10364191_T3", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1043, 1056 ] ], "normalized": [] }, { "id": "PMID-10364191_T4", "type": "Protein", "text": [ "nef" ], "offsets": [ [ 1072, 1075 ] ], "normalized": [] }, { "id": "PMID-10364191_T5", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1101, 1114 ] ], "normalized": [] }, { "id": "PMID-10364191_T6", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1313, 1326 ] ], "normalized": [] }, { "id": "PMID-10364191_T7", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1579, 1592 ] ], "normalized": [] } ]

[ { "id": "PMID-10364191_E1", "type": "Protein_catabolism", "trigger": { "text": [ "proteolysis" ], "offsets": [ [ 57, 68 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364191_T1" } ] }, { "id": "PMID-10364191_E2", "type": "Protein_catabolism", "trigger": { "text": [ "proteolysis" ], "offsets": [ [ 988, 999 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364191_T3" } ] }, { "id": "PMID-10364191_E3", "type": "Negative_regulation", "trigger": { "text": [ "resistant" ], "offsets": [ [ 1000, 1009 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364191_E2" } ] }, { "id": "PMID-10364191_E4", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 1090, 1100 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364191_T5" } ] }, { "id": "PMID-10364191_E5", "type": "Negative_regulation", "trigger": { "text": [ "attenuated" ], "offsets": [ [ 1168, 1178 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364191_E4" } ] }, { "id": "PMID-10364191_E6", "type": "Positive_regulation", "trigger": { "text": [ "maintenance" ], "offsets": [ [ 1352, 1363 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364191_T6" } ] } ]

[]

[]

[ { "id": "PMID-10364260__text", "type": "abstract", "text": [ "Human alveolar macrophages are markedly deficient in REF-1 and AP-1 DNA binding activity. \nAlthough many functions of human alveolar macrophages are altered compared with their precursor cell, the blood monocyte (monocyte), the reason(s) for these functional changes have not been determined. We recently reported that human alveolar macrophages do not express AP-1 DNA binding activity (Monick, M. M., Carter, A. B., Gudmundsson, G., Geist, L. J., and Hunninghake, G. W. (1998) Am. J. Physiol. 275, L389-L397). To determine why alveolar macrophages do not express AP-1 DNA binding activity, we first showed that there was not a decrease in expression of the FOS and JUN proteins that make up the AP-1 complex. There was, however, a significant difference in the amounts of the nuclear protein, REF-1 (which regulates AP-1 DNA binding by altering the redox status of FOS and JUN proteins), in alveolar macrophages compared with monocytes. In addition, in vitro differentiation of monocytes to a macrophage-like cell resulted in decreased amounts of REF-1. Finally, addition of REF-1 from activated monocytes to alveolar macrophage nuclear proteins resulted in a marked increase in AP-1 DNA binding. These studies strongly suggest that the process of differentiation of monocytes into alveolar macrophages is associated with a loss of REF-1 and AP-1 activity. This observation may explain, in part, some of the functional differences observed for alveolar macrophages compared with monocytes. " ], "offsets": [ [ 0, 1492 ] ] } ]

[ { "id": "PMID-10364260_T1", "type": "Protein", "text": [ "REF-1" ], "offsets": [ [ 53, 58 ] ], "normalized": [] }, { "id": "PMID-10364260_T2", "type": "Protein", "text": [ "REF-1" ], "offsets": [ [ 795, 800 ] ], "normalized": [] }, { "id": "PMID-10364260_T3", "type": "Protein", "text": [ "REF-1" ], "offsets": [ [ 1049, 1054 ] ], "normalized": [] }, { "id": "PMID-10364260_T4", "type": "Protein", "text": [ "REF-1" ], "offsets": [ [ 1077, 1082 ] ], "normalized": [] }, { "id": "PMID-10364260_T5", "type": "Protein", "text": [ "REF-1" ], "offsets": [ [ 1334, 1339 ] ], "normalized": [] } ]

[ { "id": "PMID-10364260_E1", "type": "Negative_regulation", "trigger": { "text": [ "deficient" ], "offsets": [ [ 40, 49 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364260_E2" } ] }, { "id": "PMID-10364260_E2", "type": "Binding", "trigger": { "text": [ "binding activity" ], "offsets": [ [ 72, 88 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364260_T1" } ] }, { "id": "PMID-10364260_E3", "type": "Gene_expression", "trigger": { "text": [ "in the amounts" ], "offsets": [ [ 756, 770 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364260_T2" } ] }, { "id": "PMID-10364260_E4", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 1028, 1037 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364260_T3" } ] }, { "id": "PMID-10364260_E5", "type": "Negative_regulation", "trigger": { "text": [ "loss" ], "offsets": [ [ 1326, 1330 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364260_T5" } ] } ]

[]

[]

[ { "id": "PMID-10369255__text", "type": "abstract", "text": [ "A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria [see comments] \nGenetic variation in cytokine promoter regions is postulated to influence susceptibility to infection, but the molecular mechanisms by which such polymorphisms might affect gene regulation are unknown. Through systematic DNA footprinting of the TNF (encoding tumour necrosis factor, TNF) promoter region, we have identified a single nucleotide polymorphism (SNP) that causes the helix-turn-helix transcription factor OCT-1 to bind to a novel region of complex protein-DNA interactions and alters gene expression in human monocytes. The OCT-1-binding genotype, found in approximately 5% of Africans, is associated with fourfold increased susceptibility to cerebral malaria in large case-control studies of West African and East African populations, after correction for other known TNF polymorphisms and linked HLA alleles. " ], "offsets": [ [ 0, 942 ] ] } ]

[ { "id": "PMID-10369255_T1", "type": "Protein", "text": [ "OCT-1" ], "offsets": [ [ 28, 33 ] ], "normalized": [] }, { "id": "PMID-10369255_T2", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 49, 52 ] ], "normalized": [] }, { "id": "PMID-10369255_T3", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 364, 367 ] ], "normalized": [] }, { "id": "PMID-10369255_T4", "type": "Protein", "text": [ "tumour necrosis factor" ], "offsets": [ [ 378, 400 ] ], "normalized": [] }, { "id": "PMID-10369255_T5", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 402, 405 ] ], "normalized": [] }, { "id": "PMID-10369255_T6", "type": "Protein", "text": [ "OCT-1" ], "offsets": [ [ 536, 541 ] ], "normalized": [] }, { "id": "PMID-10369255_T7", "type": "Protein", "text": [ "OCT-1" ], "offsets": [ [ 655, 660 ] ], "normalized": [] }, { "id": "PMID-10369255_T8", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 900, 903 ] ], "normalized": [] }, { "id": "PMID-10369255_T11", "type": "Entity", "text": [ "promoter region" ], "offsets": [ [ 53, 68 ] ], "normalized": [] } ]

[ { "id": "PMID-10369255_E1", "type": "Regulation", "trigger": { "text": [ "affects" ], "offsets": [ [ 20, 27 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369255_E2" } ] }, { "id": "PMID-10369255_E2", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 34, 41 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369255_T1" }, { "role": "Theme", "ref_id": "PMID-10369255_T2" }, { "role": "Site", "ref_id": "PMID-10369255_T11" } ] }, { "id": "PMID-10369255_E3", "type": "Positive_regulation", "trigger": { "text": [ "causes" ], "offsets": [ [ 487, 493 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369255_E4" } ] }, { "id": "PMID-10369255_E4", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 545, 549 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369255_T6" } ] }, { "id": "PMID-10369255_E5", "type": "Regulation", "trigger": { "text": [ "alters" ], "offsets": [ [ 608, 614 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369255_E6" } ] }, { "id": "PMID-10369255_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 620, 630 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369255_T5" } ] }, { "id": "PMID-10369255_E7", "type": "Binding", "trigger": { "text": [ "binding genotype" ], "offsets": [ [ 661, 677 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369255_T2" }, { "role": "Theme", "ref_id": "PMID-10369255_T7" }, { "role": "Site", "ref_id": "PMID-10369255_T11" } ] } ]

[ { "id": "PMID-10369255_1", "entity_ids": [ "PMID-10369255_T5", "PMID-10369255_T4" ] } ]

[]

[ { "id": "PMID-10372271__text", "type": "abstract", "text": [ "Novel therapies for inflammatory bowel disease. \nLooking back at successes and failures in newer approaches to treating IBD, it is tempting--although still difficult--to draw conclusions about pathogenesis. When a therapy proves effective, do clinicians truly know how it works? Even with a therapy as specific as anti-TNF antibody, it is not clear if the benefit is attributable to simple binding and clearance of TNF-alpha or to binding on the cell surface and subsequent deletion of the activated macrophage. When a drug appears to be less effective than preclinical models suggest, can failures in effectiveness from delivery or dosing be differentiated? The disappointing results of clinical trials with IL-10--so at odds with the prediction of benefit from animal models--bring into question the validity of those models as well as the soundness of design of the clinical trials on which efficacy of IL-10 is judged. The variability of response even to the most narrowly targeted agents suggests that these diseases are far more heterogeneous in humans than in their murine counterparts. Clinicians are only just beginning to recognize subclinical markers of response, and it may soon be possible to predict response on the basis of genetic composition. For the moment, however, the field of pharmacogenetics is embryonic. Challenges in developing new therapeutic strategies include not only identifying novel agents, but also improving the definitions of clinical endpoints and defining efficacy at the biologic level. Only through considered evaluation of clinical evidence may clinicians determine which therapies should remain novelties and which should become an accepted part of the armamentarium. " ], "offsets": [ [ 0, 1710 ] ] } ]

[ { "id": "PMID-10372271_T1", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 415, 424 ] ], "normalized": [] }, { "id": "PMID-10372271_T2", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 709, 714 ] ], "normalized": [] }, { "id": "PMID-10372271_T3", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 906, 911 ] ], "normalized": [] } ]

[ { "id": "PMID-10372271_E1", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 390, 397 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10372271_T1" } ] } ]

[]

[]

[ { "id": "PMID-10377075__text", "type": "abstract", "text": [ "PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. \nBACKGROUND: Adhesion molecule expression on the endothelial cell (EC) surface is critical for leukocyte recruitment to atherosclerotic lesions. Better understanding of transcriptional regulation of adhesion molecules in ECs may provide important insight into plaque formation. Peroxisome proliferator-activated receptor-alpha (PPARalpha), a member of the nuclear receptor family, regulates gene expression in response to certain fatty acids and fibric acid derivatives. The present study investigated PPARalpha expression in human ECs and their regulation of vascular cell adhesion molecule-1 (VCAM-1). METHODS AND RESULTS: Immunohistochemistry revealed that human carotid artery ECs express PPARalpha. Pretreatment of cultured human ECs with the PPARalpha activators fenofibrate or WY14643 inhibited TNF-alpha-induced VCAM-1 in a time- and concentration-dependent manner, an effect not seen with PPARgamma activators. Both PPARalpha activators decreased cytokine-induced VCAM-1 mRNA expression without altering its mRNA half-life. Transient transfection of deletional VCAM-1 promoter constructs and electrophoretic mobility shift assays suggest that fenofibrate inhibits VCAM-1 transcription in part by inhibiting NF-kappaB. Finally, PPARalpha activators significantly reduced adhesion of U937 cells to cultured human ECs. CONCLUSIONS: Human ECs express PPARalpha, a potentially important regulator of atherogenesis through its transcriptional control of VCAM-1 gene expression. Such findings also have implications regarding the clinical use of lipid-lowering agents, like fibric acids, which can activate PPARalpha. " ], "offsets": [ [ 0, 1739 ] ] } ]

[ { "id": "PMID-10377075_T1", "type": "Protein", "text": [ "vascular cell adhesion molecule-1" ], "offsets": [ [ 46, 79 ] ], "normalized": [] }, { "id": "PMID-10377075_T2", "type": "Protein", "text": [ "Peroxisome proliferator-activated receptor-alpha" ], "offsets": [ [ 397, 445 ] ], "normalized": [] }, { "id": "PMID-10377075_T3", "type": "Protein", "text": [ "PPARalpha" ], "offsets": [ [ 447, 456 ] ], "normalized": [] }, { "id": "PMID-10377075_T4", "type": "Protein", "text": [ "PPARalpha" ], "offsets": [ [ 621, 630 ] ], "normalized": [] }, { "id": "PMID-10377075_T5", "type": "Protein", "text": [ "vascular cell adhesion molecule-1" ], "offsets": [ [ 679, 712 ] ], "normalized": [] }, { "id": "PMID-10377075_T6", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 714, 720 ] ], "normalized": [] }, { "id": "PMID-10377075_T7", "type": "Protein", "text": [ "PPARalpha" ], "offsets": [ [ 812, 821 ] ], "normalized": [] }, { "id": "PMID-10377075_T8", "type": "Protein", "text": [ "PPARalpha" ], "offsets": [ [ 867, 876 ] ], "normalized": [] }, { "id": "PMID-10377075_T9", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 921, 930 ] ], "normalized": [] }, { "id": "PMID-10377075_T10", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 939, 945 ] ], "normalized": [] }, { "id": "PMID-10377075_T11", "type": "Protein", "text": [ "PPARgamma" ], "offsets": [ [ 1017, 1026 ] ], "normalized": [] }, { "id": "PMID-10377075_T12", "type": "Protein", "text": [ "PPARalpha" ], "offsets": [ [ 1044, 1053 ] ], "normalized": [] }, { "id": "PMID-10377075_T13", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1092, 1098 ] ], "normalized": [] }, { "id": "PMID-10377075_T14", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1189, 1195 ] ], "normalized": [] }, { "id": "PMID-10377075_T15", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1292, 1298 ] ], "normalized": [] }, { "id": "PMID-10377075_T16", "type": "Protein", "text": [ "PPARalpha" ], "offsets": [ [ 1355, 1364 ] ], "normalized": [] }, { "id": "PMID-10377075_T17", "type": "Protein", "text": [ "PPARalpha" ], "offsets": [ [ 1475, 1484 ] ], "normalized": [] }, { "id": "PMID-10377075_T18", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1576, 1582 ] ], "normalized": [] }, { "id": "PMID-10377075_T19", "type": "Protein", "text": [ "PPARalpha" ], "offsets": [ [ 1728, 1737 ] ], "normalized": [] } ]

[ { "id": "PMID-10377075_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 21, 28 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_E2" } ] }, { "id": "PMID-10377075_E2", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 38, 45 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_E3" } ] }, { "id": "PMID-10377075_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 80, 90 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_T1" } ] }, { "id": "PMID-10377075_E4", "type": "Regulation", "trigger": { "text": [ "in response to" ], "offsets": [ [ 526, 540 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_T3" } ] }, { "id": "PMID-10377075_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 631, 641 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_T4" } ] }, { "id": "PMID-10377075_E6", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 665, 675 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_T6" }, { "role": "Cause", "ref_id": "PMID-10377075_T4" } ] }, { "id": "PMID-10377075_E7", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 804, 811 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_T7" } ] }, { "id": "PMID-10377075_E8", "type": "Positive_regulation", "trigger": { "text": [ "activators" ], "offsets": [ [ 877, 887 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_T8" } ] }, { "id": "PMID-10377075_E9", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 911, 920 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_E10" } ] }, { "id": "PMID-10377075_E10", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 931, 938 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_T10" }, { "role": "Cause", "ref_id": "PMID-10377075_T9" } ] }, { "id": "PMID-10377075_E11", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 1065, 1074 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_E12" } ] }, { "id": "PMID-10377075_E12", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1084, 1091 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_E13" } ] }, { "id": "PMID-10377075_E13", "type": "Transcription", "trigger": { "text": [ "mRNA expression" ], "offsets": [ [ 1099, 1114 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_T13" } ] }, { "id": "PMID-10377075_E14", "type": "Regulation", "trigger": { "text": [ "altering" ], "offsets": [ [ 1123, 1131 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_T13" } ] }, { "id": "PMID-10377075_E15", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1299, 1312 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_T15" } ] }, { "id": "PMID-10377075_E16", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 1467, 1474 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_T17" } ] }, { "id": "PMID-10377075_E17", "type": "Regulation", "trigger": { "text": [ "transcriptional control" ], "offsets": [ [ 1549, 1572 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_E18" }, { "role": "Cause", "ref_id": "PMID-10377075_T17" } ] }, { "id": "PMID-10377075_E18", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1588, 1598 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_T18" } ] }, { "id": "PMID-10377075_E19", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 1719, 1727 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10377075_T19" } ] } ]

[ { "id": "PMID-10377075_1", "entity_ids": [ "PMID-10377075_T6", "PMID-10377075_T5" ] }, { "id": "PMID-10377075_2", "entity_ids": [ "PMID-10377075_T3", "PMID-10377075_T2" ] } ]

[]