bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutting Edge: Phosphatidylinositol 4,5-Bisphosphate Concentration at the APC Side of the Immunological Synapse Is Required for Effector T Cell Function
Authors: Fooksman David Robert , Shaikh Saame Raza , Boyle Sarah , Edidin Michael 
Published: April 2009

Abstract
Little is known about the signaling that occurs in an APC during contact with a T cell. In this article we report the concentration of the signaling lipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) at the APC side of the immunological synapse. In both human and mouse cells, a PI(4,5)P2-specific fluorescent reporter, PH-GFP (where PH is pleckstrin homology), detected an Ag-dependent enrichment of PI(4,5)P2 at the synapse between Ag-specific T cells and APC. When PIP(4,5)P2 was sequestered by a high concentration of PH-GFP reporter, cells were less susceptible to CTL-mediated lysis than control cells. These findings suggest a new regulatory target for modulating immune function that may be exploited for immune escape by pathogens and tumors.
Liver X Receptors Control IgE Expression in B Cells
Authors: Heine Guido , Dahten Anja , Hilt Kerstin , Ernst Dennis , Milovanovic Milena , Hartmann Björn , Worm Margitta 
Published: April 2009

Abstract
B lymphocytes play a fundamental role in the development of IgE-dependent allergic immune reactions. Upon appropriate activation, IgE class switch recombination is initiated in B cells, followed by terminal differentiation to IgE-secreting plasmablasts. This process is controlled by different nuclear receptors, including receptors for vitamin D, retinoids, and peroxisome proliferator-activated receptor-γ ligands. In this study, we show constitutive expression of the nuclear liver X receptor (LXR)α and LXRβ in peripheral human B cells. Activation of LXRs reduced secreted IgE (−68% ± 11) in CD40 and IL-4 activated B cells. The production of other isotypes, including IgG, IgM, IgA and B cell homeostatic parameters were not significantly altered by LXR activation. We identified inhibitory action of LXR activation on IgE production involving reduced phosphorylation of JNK and increased membrane CD23 expression (38% ± 11). The biological significance of our findings was validated by showing that systemic treatment of type I-sensitized BALB/c mice with LXR ligands reduced the serum concentrations of Ag-specific IgE in a dose-dependent manner (maximum, −52% ± 14). Thus, our data indicates that LXRs are involved in the control of IgE secretion by differentiating B cells.
HMGB1 Is Phosphorylated by Classical Protein Kinase C and Is Secreted by a Calcium-Dependent Mechanism
Authors: Oh Young Joo , Youn Ju Ho , Ji Yeounjung , Lee Sang Eun , Lim Kook Jin , Choi Ji Eun , Shin Jeon-Soo 
Published: April 2009

Abstract
High-mobility group box 1 protein (HMGB1) has been studied as a key mediator of inflammatory diseases, including sepsis. Regulating secretion is important in the control of HMGB1-mediated inflammation. Previously, it was shown that HMGB1 needs to be phosphorylated for secretion. In this study, we show that HMGB1 is phosphorylated by the classical protein kinase C (cPKC) and is secreted by a calcium-dependent mechanism. For this study, RAW264.7 cells and human peripheral blood monocytes were treated with PI3K inhibitors wortmannin, LY294002, and ZSTK474, resulting in inhibition of LPS-stimulated HMGB1 secretion, whereas inhibitors of NF-κB and MAPKs p38 and ERK showed no inhibition. Akt inhibitor IV and mammalian target of rapamycin inhibitor rapamycin did not inhibit HMGB1 secretion. However, the PKC inhibitors Gö6983 (broad-spectrum PKC), Gö6976 (cPKC), and Ro-31-7549 (cPKC) and phosphoinositide-dependent kinase 1 inhibitor, which results in protein kinase C (PKC) inhibition, inhibited LPS-stimulated HMGB1 secretion. PKC activators, PMA and bryostatin-1, enhanced HMGB1 secretion. In an in vitro kinase assay, HMGB1 was phosphorylated by recombinant cPKC and by purified nuclear cPKC from LPS-stimulated RAW264.7 cells, but not by casein kinase II or cdc2. HMGB1 secretion was also induced by the calcium ionophore A23187 and inhibited by the Ca2+ chelators BAPTA-AM and EGTA. These findings support a role for Ca2+-dependent PKC in HMGB1 secretion. Thus, we propose that cPKC is an effector kinase of HMGB1 phosphorylation in LPS-stimulated monocytes and PI3K-phosphoinositide-dependent kinase 1 may act in concert to control HMGB1 secretion independent of the NF-κB, p38, and ERK pathways.
Matrix Metalloproteinase-1 Is Regulated in Tuberculosis by a p38 MAPK-Dependent,p-Aminosalicylic Acid-Sensitive Signaling Cascade
Authors: Rand Lucinda , Green Justin A. , Saraiva Luísa , Friedland Jon S. , Elkington Paul T. G. 
Published: April 2009

AbstractMycobacterium tuberculosis (M. tb) must cause lung disease to spread. Matrix metalloproteinases (MMPs) degrade the extracellular matrix and are implicated in tuberculosis-driven tissue destruction. We investigated signaling pathways regulating macrophage MMP-1 and -7 in human pulmonary tuberculosis and examine the hypothesis that the antimycobacterial drug p-aminosalicylic acid acts by inhibiting such pathways. In primary human macrophages, M. tb up-regulates gene expression and secretion of MMP-1 (interstitial collagenase) and MMP-7 (matrilysin). In tuberculosis patients, immunohistochemical analysis of lung biopsies demonstrates that p38 MAPK is phosphorylated in macrophages surrounding granulomas. In vitro, M. tb drives p38 phosphorylation. p38 inhibition suppresses M. tb-dependent MMP-1 secretion by 57.8% and concurrently increases secretion of its specific inhibitor TIMP-1 by 243.7%, demonstrating that p38 activity regulates matrix degradation by macrophages. p38 signals downstream to the cyclooxygenase 2/PGE2 pathway. p-Aminosalicyclic acid, an agent used to treat drug-resistant tuberculosis, inhibits M. tb-driven MMP-1 but not MMP-7 gene expression and secretion. PAS acts by blocking PGE2 production without affecting M. tb growth. In summary, p-aminosalicyclic acid decreases MMP-1 activity by inhibiting a p38 MAPK-PG signaling cascade, suggesting that this pathway is a therapeutic target to reduce inflammatory tissue destruction in tuberculosis.
The Innate Immune Response Affects the Development of the Autoimmune Response in Theiler’s Virus-Induced Demyelinating Disease
Authors: Olson Julie K. , Miller Stephen D. 
Published: April 2009

Abstract
Multiple sclerosis (MS) is a human CNS autoimmune demyelinating disease. Epidemiological evidence has suggested a role for virus infection in the initiation and/or exacerbation of MS. Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease serves as a relevant mouse model for MS. TMEV-infected mice develop a demyelinating disease with clinical symptoms beginning around 35 days after infection, which is associated with development of myelin-specific, PLP139–151, CD4+ T cell responses. Viruses have been suggested to initiate autoimmune disease through bystander activation of immune cells or through bystander damage to tissue during infection. We examined the effect of the innate immune response on development of autoimmune demyelinating disease by altering the innate immune response through administration of innate immune cytokines, IFN-α or IFN-β, or antiserum against the type I IFNs during the innate immune response to TMEV. Administration of IFN-β, but not IFN-α, to TMEV- infected mice led to reduced myelin-specific CD4+ T cell responses and reduced demyelinating disease, which was associated with decreased immune cell infiltration into the CNS and increased expression of IL-10 in the CNS. Conversely, administration of antiserum to IFN-β led to a more severe demyelinating disease. In addition, administration of poly(I:C), which is an innate immune agonist, to TMEV-infected mice during the innate immune response resulted in decreased myelin-specific CD4+ T cell responses and reduced demyelinating disease. These results demonstrate that activating or enhancing the innate immune response can reduce the subsequent initiation and progression of the autoimmune response and demyelinating disease.
Cutting Edge: Rescue of Pre-TCR but Not Mature TCR Signaling in Mice Expressing Membrane-Targeted SLP-76
Authors: Bezman Natalie A. , Baker Rebecca G. , Lenox Laurie E. , Jordan Martha S. , Koretzky Gary A. 
Published: April 2009

Abstract
SLP-76 (Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa) organizes signaling from immunoreceptors, including the platelet collagen receptor, the pre-TCR, and the TCR, and is required for T cell development. In this study we examine a mouse in which wild-type SLP-76 is replaced with a mutant constitutively targeted to the cell membrane. Membrane-targeted SLP-76 (MTS) supports ITAM signaling in platelets and from the pre-TCR. Signaling from the mature TCR, however, is defective in MTS thymocytes, resulting in failed T cell differentiation. Defective thymic selection by MTS is not rescued by a SLP-76 mutant whose localization is restricted to the cytosol. Thus, fixed localization of SLP-76 reveals differential requirements for the subcellular localization of signaling complexes downstream of the pre-TCR vs mature TCR.
ATLa, an Aspirin-Triggered Lipoxin A4 Synthetic Analog, Prevents the Inflammatory and Fibrotic Effects of Bleomycin-Induced Pulmonary Fibrosis
Authors: Martins Vanessa , Valença Samuel S. , Farias-Filho Francisco A. , Molinaro Raphael , Simões Rafael L. , Ferreira Tatiana P. T. , e Silva Patrícia M. R. , Hogaboam Cory M. , Kunkel Steven L. , Fierro Iolanda M. , Canetti Claudio , Benjamim Claudia F. 
Published: April 2009

Abstract
Despite an increase in the knowledge of mechanisms and mediators involved in pulmonary fibrosis, there are no successful therapeutics available. Lipoxins (LX) and their 15-epimers, aspirin-triggered LX (ATL), are endogenously produced eicosanoids with potent anti-inflammatory and proresolution effects. To date, few studies have been performed regarding their effect on pulmonary fibrosis. In the present study, using C57BL/6 mice, we report that bleomycin (BLM)-induced lung fibrosis was prevented by the concomitant treatment with an ATL synthetic analog, ATLa, which reduced inflammation and matrix deposition. ATLa inhibited BLM-induced leukocyte accumulation and alveolar collapse as evaluated by histology and morphometrical analysis. Moreover, Sirius red staining and lung hydroxyproline content showed an increased collagen deposition in mice receiving BLM alone that was decreased upon treatment with the analog. These effects resulted in benefits to pulmonary mechanics, as ATLa brought to normal levels both lung resistance and compliance. Furthermore, the analog improved mouse survival, suggesting an important role for the LX pathway in the control of disease establishment and progression. One possible mechanism by which ATLa restrained fibrosis was suggested by the finding that BLM-induced myofibroblast accumulation/differentiation in the lung parenchyma was also reduced by both simultaneous and posttreatment with the analog (α-actin immunohistochemistry). Interestingly, ATLa posttreatment (4 days after BLM) showed similar inhibitory effects on inflammation and matrix deposition, besides the TGF-β level reduction in the lung, reinforcing an antifibrotic effect. In conclusion, our findings show that LX and ATL can be considered as promising therapeutic approaches to lung fibrotic diseases.
Conditional Gene Targeting in Mouse High Endothelial Venules
Authors: Kawashima Hiroto , Hirakawa Jotaro , Tobisawa Yuki , Fukuda Minoru , Saga Yumiko 
Published: April 2009

Abstract
High endothelial venules (HEVs) are specialized blood vessels of secondary lymphoid organs composed of endothelial cells with a characteristic cuboidal morphology. Lymphocytes selectively adhere to and migrate across HEVs to initiate immune responses. In this study, we established a novel transgenic mouse line expressing Cre recombinase under the transcriptional control of the gene encoding HEV-expressed sulfotransferase, N-acetylglucosamine-6-O-sulfotransferase 2 (GlcNAc6ST-2), using bacterial artificial chromosome recombineering. Crossing these transgenic mice with the ROSA26 reporter strain, which expresses lacZ following Cre-mediated recombination, and staining the resulting progeny with 5-bromo-4-chloro-5-indolyl-β-d-galactoside indicated that Cre recombinase was specifically expressed in mAb MECA79-reactive HEVs in secondary lymphoid organs but not in any other blood vessels of the transgenic mice. The expression of Cre recombinase correlated with a developmental switch, from immature, mAb MECA367-reactive HEVs to mature, mAb MECA79-reactive HEVs in neonatal lymph nodes. In addition to the HEVs, Cre recombinase was also strongly expressed in the colonic villi, which recapitulated the intrinsic expression of GlcNAc6ST-2 as confirmed in GlcNAc6ST-2GFP/GFP knock-in mice and by RT-PCR. Furthermore, treatment with an antimicrobial agent revealed that the colonic expression of Cre recombinase in the transgenic mice was regulated by commensal bacteria in the colon. In addition, Cre recombinase was expressed in a small subset of cells in the brain, testis, stomach, small intestine, and lung. In view of the restricted expression of Cre recombinase, this transgenic mouse line should be useful for elucidating tissue-specific gene functions using the Cre/loxP system.
The Major Outer Membrane Protein of a Periodontopathogen Induces IFN-β and IFN-Stimulated Genes in Monocytes via Lipid Raft and TANK-Binding Kinase 1/IFN Regulatory Factor-3
Authors: Lee Sung-Hoon , Kim Joong Su , Jun Hye-Kyoung , Lee Hae-Ri , Lee Daesil , Choi Bong-Kyu 
Published: April 2009

Abstract
Surface molecules of pathogens play an important role in stimulating host immune responses. Elucidation of the signaling pathways activated by critical surface molecules in host cells provides insight into the molecular pathogenesis resulting from bacteria-host interactions. MspTL is the most abundant outer membrane protein of Treponema lecithinolyticum, which is associated with periodontitis, and induces expression of a variety of proinflammatory factors. Although bacteria and bacterial components like LPS and flagellin are known to induce IFN-β, induction by bacterial surface proteins has not been reported. In the present study, we investigated MspTL-mediated activation of signaling pathways stimulating up-regulation of IFN-β and IFN-stimulated genes in a human monocytic cell line, THP-1 cells, and primary cultured human gingival fibroblasts. MspTL treatment of the cells induced IFN-β and the IFN-stimulated genes IFN-γ-inducible protein-10 (IP-10) and RANTES. A neutralizing anti-IFN-β Ab significantly reduced the expression of IP-10 and RANTES, as well as STAT-1 activation, which was also induced by MspTL. Experiments using specific small interfering RNA showed that MspTL activated TANK-binding kinase 1 (TBK1), but not inducible IκB kinase (IKKi). MspTL also induced dimerization of IFN regulatory factor-3 (IRF-3) and translocation into the nucleus. The lipid rapid-disrupting agents methyl-β-cyclodextrin, nystatin, and filipin inhibited the MspTL internalization and cellular responses, demonstrating that lipid raft activation was a prerequisite for MspTL cellular signaling. Our results demonstrate that MspTL, the major outer protein of T. lecithinolyticum, induced IFN-β expression and subsequent up-regulation of IP-10 and RANTES via TBK1/IRF-3/STAT-1 signaling secondary to lipid raft activation.
Protective CD8 T Cell Memory Is Impaired during Chronic CD70-Driven Costimulation
Authors: van Gisbergen Klaas P. J. M. , van Olffen Ronald W. , van Beek Josine , van der Sluijs Koenraad F. , Arens Ramon , Nolte Martijn A. , van Lier Rene A. 
Published: April 2009

Abstract
Chronic infection results in continuous formation and exhaustion of effector CD8 T cells and in failure of memory CD8 T cell development. Expression of CD70 and other molecules that provide costimulation to T cells is maintained during chronic infection. To analyze the impact of constitutive CD70-driven costimulation, we generated transgenic mice expressing CD70 specifically on T cells. We show that CD70 promoted accumulation of CD8 T cells with characteristics strikingly similar to exhausted effector CD8 T cells found during chronic infection. CD70 on T cells provided costimulation that enhanced primary CD8 T cell responses against influenza. In contrast, memory CD8 T cell maintenance and protection against secondary challenge with influenza was impaired. Interestingly, we found no effect on the formation of either effector or memory CD4 T cells. We conclude that constitutive expression of CD70 is sufficient to deregulate the CD8 T cell differentiation pathway of acute infection reminiscent of events in chronic infection.
TRBP Homolog Interacts with Eukaryotic Initiation Factor 6 (eIF6) in Fenneropenaeus chinensis
Authors: Wang Shuai , Liu Ning , Chen An-Jing , Zhao Xiao-Fan , Wang Jin-Xing 
Published: April 2009

Abstract
The HIV transactivating response RNA-binding protein (TRBP) plays an important role in many biological processes. We have cloned three cDNAs from newly identified genes in the TRBP family from Fenneropenaeus chinensis. These genes have been designated Fc-TRBP1–3. Recombinant Fc-TRBP1, which was produced in Escherichia coli, was used for panning of a T7 phage display library of the Chinese shrimp hemocytes. From this panning, Fc-eukaryotic initiation factor 6 (Fc-eIF6) was isolated and sequenced. Fc-eIF6 was then cloned, recombinantly expressed, and shown to interact with Fc-TRBP by the performance of pull-down assays and Far Western blot analysis. Expression of Fc-TRBP was detected in many tissues, with elevated expression in the heart, gill, and intestine in the early stages of infection by the white spot syndrome virus (WSSV), and enhanced expression in most tissues following challenge with Vibrio anguillarum. Western blot studies confirmed the increased expression of Fc-TRBP in the gill after WSSV infection. The expression pattern of eIF6 was also analyzed and its expression was also up-regulated in intestine of WSSV-challenged shrimp. The replication of WSSV was reduced after injection of Fc-TRBP. These results indicate that Fc-TRBP and Fc-eIF6 may be components of the RNA-induced silencing complex (RISC), and thereby play a crucial role in the antiviral defense response of shrimp.
Imiquimod-Induced Psoriasis-Like Skin Inflammation in Mice Is Mediated via the IL-23/IL-17 Axis
Authors: van der Fits Leslie , Mourits Sabine , Voerman Jane S. A. , Kant Marius , Boon Louis , Laman Jon D. , Cornelissen Ferry , Mus Anne-Marie , Florencia Edwin , Prens Errol P. , Lubberts Erik 
Published: April 2009

Abstract
Topical application of imiquimod (IMQ), a TLR7/8 ligand and potent immune activator, can induce and exacerbate psoriasis, a chronic inflammatory skin disorder. Recently, a crucial role was proposed for the IL-23/IL-17 axis in psoriasis. We hypothesized that IMQ-induced dermatitis in mice can serve as a model for the analysis of pathogenic mechanisms in psoriasis-like dermatitis and assessed its IL-23/IL-17 axis dependency. Daily application of IMQ on mouse back skin induced inflamed scaly skin lesions resembling plaque type psoriasis. These lesions showed increased epidermal proliferation, abnormal differentiation, epidermal accumulation of neutrophils in microabcesses, neoangiogenesis, and infiltrates consisting of CD4+ T cells, CD11c+ dendritic cells, and plasmacytoid dendritic cells. IMQ induced epidermal expression of IL-23, IL-17A, and IL-17F, as well as an increase in splenic Th17 cells. IMQ-induced dermatitis was partially dependent on the presence of T cells, whereas disease development was almost completely blocked in mice deficient for IL-23 or the IL-17 receptor, demonstrating a pivotal role of the IL-23/IL-17 axis. In conclusion, the sole application of the innate TLR7/8 ligand IMQ rapidly induces a dermatitis closely resembling human psoriasis, critically dependent on the IL-23/IL-17 axis. This rapid and convenient model allows further elucidation of pathogenic mechanisms and evaluation of new therapies in psoriasis.
Amyloid β Interaction with Receptor for Advanced Glycation End Products Up-Regulates Brain Endothelial CCR5 Expression and Promotes T Cells Crossing the Blood-Brain Barrier
Authors: Li Man , Shang De-Shu , Zhao Wei-Dong , Tian Li , Li Bo , Fang Wen-Gang , Zhu Li , Man Shu-Mei , Chen Yu-Hua 
Published: April 2009

Abstract
How circulating T cells infiltrate into the brain in Alzheimer disease (AD) remains unclear. We previously reported that amyloid β (Aβ)-dependent CCR5 expression in brain endothelial cells is involved in T cell transendothelial migration. In this study, we explored the signaling pathway of CCR5 up-regulation by Aβ. We showed that inhibitors of JNK, ERK, and PI3K significantly decreased Aβ-induced CCR5 expression in human brain microvascular endothelial cells (HBMECs). Chromatin immunoprecipitation assay revealed that Aβ-activated JNK, ERK, and PI3K promoted brain endothelial CCR5 expression via transcription factor Egr-1. Furthermore, neutralization Ab of receptor for advanced glycation end products (RAGE; an Aβ receptor) effectively blocked Aβ-induced JNK, ERK, and PI3K activation, contributing to CCR5 expression in HBMECs. Aβ fails to induce CCR5 expression when truncated RAGE was overexpressed in HBMECs. Transendothelial migration assay showed that the migration of MIP-1α (a CCR5 ligand)-expressing AD patients’ T cells through in vitro blood-brain barrier model was effectively blocked by anti-RAGE Ab, overexpression of truncated RAGE, and dominant-negative PI3K, JNK/ERK, or Egr-1 RNA interference in HBMECs, respectively. Importantly, blockage of intracerebral RAGE abolished the up-regulation of CCR5 on brain endothelial cells and the increased T cell infiltration in the brain induced by Aβ injection in rat hippocampus. Our results suggest that intracerebral Aβ interaction with RAGE at BBB up-regulates endothelial CCR5 expression and causes circulating T cell infiltration in the brain in AD. This study may provide a new insight into the understanding of inflammation in the progress of AD.
Expression of CD226 Antagonizes Apoptotic Cell Death in Murine Thymocytes
Authors: Fang Liang , Zhang Xinhai , Miao Jun , Zhao Fang , Yang Kun , Zhuang Ran , Bujard Hermann , Wei Yanzhang , Yang Angang , Chen Lihua , Jin Boquan 
Published: April 2009

Abstract
CD226 is known to be expressed on many types of peripheral lymphoid cells and involved in T cell differentiation, activation, and cytotoxicity. In this study, we report that CD226 is also expressed on mouse thymocytes at varying developmental stages, and its expression is associated with resistance of thymocytes to apoptosis. The levels of CD226 expression appeared to be closely coupled with thymocyte development, in that it was preferentially expressed on CD4+CD8− and CD4−CD8+ thymocytes at all stages during mouse development, and was markedly increased on the cells in neonatal mice. Of the CD4+CD8+ population, CD226 was predominantly expressed by the cells also positive for CD69, suggesting that CD226 expression may be induced in thymocyte-positive selection. Inhibition of CD226 by short hairpin RNA in a fetal thymus organ culture model led to reduced thymus cellularity, which was associated with enhanced apoptotic cell death. In contrast, CD226-transgenic mice displayed enlarged thymus lobes resulting from increased thymus cellularity. CD226 on thymocytes seemed to play a role in regulating the expression of survivin, as inhibition of CD226 down-regulated survivin, but overexpression of CD226 rescued thymocytes from apoptosis through up-regulation of survivin. In addition, overexpression of CD226 reduced sensitivity of EL-4 thymoma cells to apoptosis by up-regulating the expression of survivin. Taken together, these results indicate that CD226 is an antiapoptotic molecule and may play an important role in murine thymocyte development.