bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) demonstrates structural and functional similarities to the alpha 4 beta 7-integrin binding domains of murine MAdCAM-1, but extreme divergence of mucin-like sequences.
Authors: Shyjan A M , Bertagnolli M , Kenney C J , Briskin M J 
Published: December 2022

Abstract
The mucosal vascular addressin, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), is an Ig family adhesion receptor preferentially expressed by venular endothelial cells at sites of lymphocyte extravasation in murine mucosal lymphoid tissues and lamina propria. MAdCAM-1 specifically binds both human and mouse lymphocytes that express the homing receptor for Peyer's patches, the integrin alpha 4 beta 7. Functional expression cloning was used to isolate a cDNA from a macaque mesenteric lymph node library that encodes the homologue to murine MAdCAM-1. The macaque cDNA was subsequently used to clone the human homologue as well. Expression of human MAdCAM-1 RNA is restricted to mucosal tissues, gut-associated lymphoid tissues and spleen. Human MAdCAM-1 selectively binds both murine and human lymphocyte cell lines expressing alpha 4 beta 7. Human and macaque MAdCAM-1 have two Ig-like domains that are similar to the two amino-terminal integrin binding domains of murine MAdCAM-1. The conservation of sequences within the region homologous to the mucin/IgA domain of murine MAdCAM-1 is, however, much less apparent. These receptors exhibit considerable variation from murine MAdCAM-1 with respect to the length of the mucin-like sequence and the lack of a membrane proximal Ig (IgA-like) domain. The isolation of these different species of MAdCAM-1 demonstrates greater seleoffctive pressure for maintenance of amino acids involved in alpha 4 beta 7 binding than those sequences presumably involved in the presentation of carbohydrates for selectin binding.
A carbohydrate structure associated with CD15 (Lewis x) on myeloid cells is a novel ligand for human CD2.
Authors: Warren H S , Altin J G , Waldron J C , Kinnear B F , Parish C R 
Published: December 2022

Abstract
The T cell and NK cell adhesion molecule CD2 interacts with different ligands, viz, CD58, CD48, and CD59. Using a fluorescent multimeric construct of rCD2, we previously identified an additional CD2 ligand (CD2L) on the erythroleukemic cell line K562. CD2L bound to a different region of CD2 than known ligands and was N-glycosylation dependent. In this study we show that mAbs specific for the carbohydrate Ag Lewis x (CD15, Gal-beta 1-4 GlcNAc alpha 1-3Fuc) inhibit multimeric rCD2 binding to CD2L. CD2L is restricted in expression to myeloid cells, where it is co-expressed with CD58 on monocytes and is the dominant, if not sole, CD2 ligand on neutrophils. Sugar specificity studies show that CD2L is not CD15. Thus, whereas soluble Lewis x inhibits binding of CD15 mAb to K562 and neutrophils, binding of multimeric rCD2 is unaffected. Furthermore, multimeric rCD2 binding to K562 is inhibited by L-fucose and following treatment of K562 with an alpha 1-6 fucosidase, whereas these treatments do not inhibit the binding of CD15 mAb. Thus, it is likely that CD2L is a carbohydrate structure closely associated with, yet distinct from, CD15, which can be sterically blocked by CD15 mAb. Functional studies revealed that CD2L is probably an important CD2 ligand in the non-MHC-restricted NK cell killing of K562 target cells, since this activity was strongly inhibited by CD15 mAb. Collectively, this study indicates that a CD15 (Lewis x)-associated carbohydrate structure(s), which has previously been shown to be a selectin ligand, also may function as an important CD2 ligand on myeloid cells.
Transforming growth factor-beta 1 is the predominant paracrine inhibitor of macrophage cytokine synthesis produced by glomerular mesangial cells .
Authors: Kitamura M , Sütö T , Yokoo T , Shimizu F , Fine L G 
Published: December 2022

Abstract
Cross-communication between glomerular cells and infiltrating mononuclear cells plays an important role in the generation of or recovery from glomerular diseases. We found that cultured mesangial cells secrete a factor that inhibits production of proinflammatory cytokines by activated macrophages. Treatment of J774.2 macrophages with conditioned media from rat mesangial cells blunted the transcriptional induction of IL-1 beta, IL-6, and TNF-alpha by LPS. None of the media conditioned by other fibroblastic, epithelial, or endothelial cell lines exhibited the inhibitory effect. Media conditioned by normal rat glomeruli contained a similar inhibitory activity, which was enhanced in an acute model of mesangial proliferative glomerulonephritis. To identify the active component involved, we examined the expression of known macrophage deactivators IL-10, IL-13, and TGF-beta 1 in mesangial cells. Under the basal culture conditions, strong expression of TGF-beta 1 mRNA was observed, whereas expression of neither IL-10 nor IL-13 was detected. Immunoblot analysis and a specific bioassay detected the active form of TGF-beta 1 exclusively in the mesangial cell conditioned media. The inhibitory activity was enhanced by heat treatment, consistent with the known property of TGF-beta. A specific anti-TGF-beta 1 neutralizing Ab abolished the inhibitory effect exerted by the mesangial cell media, and exogenously added TGF-beta1 suppressed macrophage cytokine expression in a dose-dependent manner. These findings demonstrate that mesangial cells and isolated glomeruli secrete a factor which suppresses cytokine expression by activated macrophages, the active entity being identified as TGF-beta 1.
IL-13 induces phosphorylation and activation of JAK2 Janus kinase in human colon carcinoma cell lines: similarities between IL-4 and IL-13 signaling.
Authors: Murata T , Noguchi P D , Puri R K 
Published: December 2022

Abstract
We have recently reported that IL-13R may share a component with IL-4R. Here we report that both IL-4 and IL-13 share signaling events in human colon carcinoma cell lines (HT-29 and WiDr). IL-13 caused rapid phosphorylation of the three out of four members of the known Janus family of kinases (JAKs). We show that JAK2 kinase is rapidly phosphorylated and activated in response to IL-13. Within 1 min of activation, JAK2 was phosphorylated, and peaked in 10 min. In addition, IL-13 phosphorylated insulin response substrate-1, IL-4R p140, JAK1, and Tyk2, but not JAK3 kinase. IL-4 also stimulated all three kinases and substrates, but unlike in immune cells, IL-4 did not involve JAK3 activation for its signaling in colon cancer cell lines. Furthermore, JAK2 associated with the IL-4R p140 before and after stimulation with IL-13. Both IL-13 and IL-4 induced phosphorylation of IL-4 STAT (STAT6) but not STAT1, STAT3, or STAT5. 125I-IL-13 did not bind to colon cancer cell lines, but unlabeled IL-13 competed for the binding of 125I-IL-4. Our data suggest that IL-13 utilizes IL-4R and its signaling pathway, and JAK2 may play an important role in the function of IL-4R and IL-13R in colon cancer cells.
In vivo effects of chicken myelomonocytic growth factor: delivery via a viral vector.
Authors: York J J , Strom A D , Connick T E , McWaters P G , Boyle D B , Lowenthal J W 
Published: December 2022

Abstract
We have constructed a recombinant fowlpox virus (FPV) that expresses chicken myelomonocytic growth factor (cMGF). Administration of this construct (fp/cMGF) to 1-day-old chicks resulted in a marked and sustained increase in the number of circulating blood monocytes compared with chicks infected with the parental FPV strain (fp/M3). Blood monocyte numbers were elevated within 4 days of fp/cMGF infection, reached maximal levels at day 9, and returned to normal levels by day 16. During the peak response, approximately 35% of blood leukocytes were monocytes, compared with 4 to 7% in uninfected control birds. Infection with fp/M3 also resulted in a detectable increase in monocyte numbers; however, the effect was less dramatic. Compared with fp/M3, fp/cMGF consistently induced two- to threefold higher monocyte numbers, and the period of monocytosis was longer (10 vs 5 days). No other specific changes in white blood cell populations were observed. Associated with the increase in the number of monocytes was an increase in their state of activation, as measured by the ability to produce nitric oxide (NO) and to phagocytose latex beads. Blood monocytes from birds infected with fp/cMGF produced about 6 times as much NO per cell compared with monocytes from fp/M3-infected birds. Monocytes from normal birds failed to produce detectable levels of NO. Furthermore, cMGF treatment specifically induced enhanced phagocytic activity in blood monocytes. Overall, these results indicate that viral vectors are suitable for the delivery of biologically active cytokines and that they allow an assessment of cytokine activities in vivo.
Encephalitogenic epitopes of myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein for experimental allergic encephalomyelitis induction in Biozzi ABH (H-2Ag7) mice share an amino acid motif.
Authors: Amor S , O'Neill J K , Morris M M , Smith R M , Wraith D C , Groome N , Travers P J , Baker D 
Published: December 2022

Abstract
Myelin basic protein (MBP) and synthetic MBP peptides were screened for their ability to induce experimental allergic encephalomyelitis in Biozzi ABH (H-2Ag7) mice. In contrast to the failure of native MBP to induce experimental allergic encephalomyelitis, the use of overlapping MBP peptides revealed epitopes within MBP 12-26 and MBP 21-35, which induced mild disease. In comparison with disease induced by spinal cord homogenate or peptides of myelin oligodendrocyte glycoprotein (MOG) or proteolipid protein (PLP), the low incidence indicates that, at least in ABH mice, MBP is a minor encephalitogen. However, the data suggest the presence of a peptide core between MBP 21-26 (HARHGF), which contains similar elements to the previously defined encephalitogenic MOG 1-22 and PLP 56-70 peptides. The fine specificity of these epitopes was further investigated using frame-shifted peptides, which indicated cores between MOG 9-15 (GYPIRAL) and PLP 62-68 (NVIHAFQ). Based on these pathogenic peptides, a putative H-2Ag7 binding motif is suggested that contains a series of hydrophobic, basic, small, and large hydrophobic residues within a 6 to 7 amino acid core. The core and particular importance of these four residues in PLP 56-70 was confirmed in vitro using amino acid substitution studies. These findings support many of the predictions made by computer modeling of peptide:H-2Ag7 interactions. This may have relevance in the design of strategies in the treatment of experimental autoimmune diseases in animals that express this haplotype.
Structural elements controlling anti-DNA antibody affinity and their relationship to anti-phosphorylcholine activity.
Authors: Pewzner-Jung Y , Simon T , Eilat D 
Published: December 2022

Abstract
The heavy chains of the anti-DNA autoantibody D42, derived from an autoimmune NZB/NZW F1 mouse, and the anti-phosphorylcholine (PC) Ab 6G6, obtained from an immunized CBA/J mouse, are both encoded by the same VH11 (S107) germ-line gene. We have combined VH CDR3 exchange, site-directed mutagenesis, transfection of mutant hybridoma cells, and equilibrium affinity measurements of the expressed Abs to analyze the contribution of germ line-encoded genetic elements and somatic mutations to DNA binding affinity as well as to test the possibility that an anti-PC Ab can be converted to an anti-DNA Ab by somatic mutation. Our results indicate that the major contribution to DNA binding affinity is provided by the nonmutated rearranged configuration of the autoantibody and depends on the particular H/L chain pairing and the structure of the VH CDR3 gene segment. Two heavy chain somatic mutations increased the DNA binding affinity of the D42 anti-DNA Ab by about 10-fold. One of these mutations abolished PC binding of the 6G6 Ab, but did not convert it to an anti-DNA. These results suggest that activation of autoreactive B cells bearing germ-line-encoded Ag receptors may be required to initiate the affinity maturation of an anti-DNA response, and that B cells responding by somatic mutation to external Ags, such as PC, may be unable to contribute significantly to the high affinity immune response that is typical of disease-related anti-DNA autoantibodies.
CD2-induced apoptosis in activated human peripheral T cells: a Fas-independent pathway that requires early protein tyrosine phosphorylation.
Authors: Mollereau B , Deckert M , Déas O , Rieux-Laucat F , Hirsch F , Bernard A , Fischer A , Lynch D H , Charpentier B , Le Deist F , Senik A 
Published: December 2022

Abstract
Short-term activated peripheral T lymphocytes are susceptible to apoptotic cell death triggered by CD2 mAbs. The aim of this study was to examine whether the CD2-mediated pathway of apoptosis is linked to the Fas death pathway, as this is the case for CD3/TCR-triggered apoptosis in several models of T cells. Using T lymphocytes from patients harboring Fas gene mutations and displaying a profound defect in Fas signaling of cell death, we show that CD2- (but not CD3-) mediated apoptosis still proceeds normally. In normal activated T cells, CD3-mediated apoptosis is prevented by reagents that block the Fas/Fas-ligand interaction, namely soluble M3 (an antagonistic anti-Fas mAb) and soluble human Fas.Fc, a fusion protein able to bind released Fas-ligand. In contrast, CD2 signaling of apoptosis resists these blocking agents. Neither new protein synthesis nor the activation of calcineurin was required for CD2- and Fas-mediated apoptosis, suggesting that latent cytoplasmic "death" molecules were activated upon stimulation of the cells. In both cases, protein tyrosine kinases were transiently activated, as is exemplified by the autophosphorylation and exokinase activity of p56lck, yielding overlapping yet nonidentical profiles of protein tyrosine phosphorylation. Pretreating the cells with herbimycin A, before the addition of the apoptotic stimuli, almost completely inhibited CD2 transmembrane signaling of apoptosis, but left intact Fas-induced apoptosis. Our data suggest that CD2 is a Fas-independent cell death pathway that might contribute directly to the elimination of T cells expanding during an immune reaction.
CD28-mediated cytotoxicity by the human leukemic NK cell line YT involves tyrosine phosphorylation, activation of phosphatidylinositol 3-kinase, and protein kinase C.
Authors: Teng J M , Liu X R , Mills G B , Dupont B 
Published: December 2022

Abstract
The human leukemic cell line YT displays spontaneous cytotoxicity against CD80+ and/or CD86+ and ICAM-1+ target cells. In this work, we report that CD28-mediated cytotoxicity of YT involves tyrosine phosphorylation and activation of phosphatidylinositol (PI) 3-kinase, the Tec kinase Itk/Emt, and protein kinase C (PKC). YT mediates lysis of CD80+/CD86+ B lymphoblastoid cell lines and the murine mastocytoma p815 transfected with CD80 or CD86. The lysis was inhibited by two different Pi 3-kinase inhibitors, wortmannin and LY294002. The PKC inhibitors calphostin C and bisindolylmaleimide GF109203X also abolished YT-mediated cytotoxicity. Furthermore, exocytosis of cytolytic effector molecules was also inhibited by PI 3-kinase inhibitors and PKC inhibitors. PMA together with Ionomycin did not induce granule exocytosis or cytotoxicity by YT cells. Treatment of YT cells with PMA for up to 20 h, which depleted PMA-responsive PKC isoforms, had no effect on the CD28-mediated cytotoxicity. This cytotoxicity displayed by PMA-treated YT cells, however, could still be inhibited by Pi 3-kinase inhibitors and PKC inhibitors. Taken together, these results are consistent with a model in which activation of CD28 and LFA-1 induces tyrosine phosphorylation of the CD28 cytoplasmic domain, recruitment and activation of PI 3-kinase, as well as the Tec kinase Itk/Emt, and the activation of PMA-nonresponsive PKC isoenzymes. Activation of PI 3-kinase and PMA-nonresponsive PKC isoenzymes is shown to be involved directly in cytolytic granule release by YT cells.
Vasoactive intestinal peptide inhibits IL-4 production in murine T cells by a post-transcriptional mechanism.
Authors: Wang H Y , Xin Z , Tang H , Ganea D 
Published: December 2022

Abstract
Vasoactive intestinal peptide (VIP), a neuropeptide present in the peptidergic innervation of lymphoid organs and expressed in thymocytes and peripheral lymphocytes, modulates cytokine expression in T lymphocytes. VIP down-regulates the expression of IL-2 and IL-10 mRNA in T cells stimulated through the TCR-associated CD3 complex. In contrast, IL-4 production is inhibited at a post-transcriptional level. In this study, we investigate the molecular mechanisms involved in the inhibition of IL-4 production by VIP. At the protein level, the time courses for IL-2 and IL-4 inhibition by VIP are different, with IL-4 being affected approximately 24 h later than IL-2. Northern blots and competitive reverse-transcription PCR analysis confirm the post-transcriptional inhibition of IL-4 production in both murine spleen cells and thymocytes activated through the CD3 complex. VIP does not affect IL-4 secretion, and does not induce a rapid IL-4 reuptake. Exogenous rIL-2 completely reverses the inhibitory effect of VIP, suggesting that VIP inhibits IL-4 production indirectly as a consequence of IL-2 inhibition. Studies regarding the newly synthesized IL-4 protein show that although VIP and exogenous IL-2 do not affect the rate of IL-4 synthesis, VIP reduces significantly the stability of the newly synthesized IL-4 protein, and exogenous IL-2 can restore it to the levels observed in activated cells in the absence of VIP. These results explore the molecular mechanisms involved in the neuroendocrine regulation of cytokine production, and support the idea that neuropeptides released or produced in the local lymphoid microenvironment may participate in the intricate cytokine network controlling local immune responses.
The COI mitochondrial gene encodes a minor histocompatibility antigen presented by H2-M3.
Authors: Morse M C , Bleau G , Dabhi V M , Hétu F , Drobetsky E A , Lindahl K F , Perreault C 
Published: December 2022

Abstract
We found that (LP x C57BL/6)F1 mice could raise a CTL response against parental C57BL/6 cells. These CTLs recognized a maternally transmitted, H2-M3wt-restricted, minor histocompatibility Ag (MiHA) that is widely distributed among many strains of mice and encoded by the COI mitochondrial gene. The wild-type MiHA is the COI N-terminal hexapeptide. Sequencing the 5' end of the COI gene in LP and C57BL/6 mice showed that the LP allele arose by a T--&gt;C transition in the third codon, which caused substitution of threonine for isoleucine. Molecular characterization of this MiHA and the demonstration that it is presented exclusively by H2-M3: 1) support the concept that differential expression of MiHA in MHC-identical animals is caused by polymorphism of the MiHA gene proper; 2) expand our knowledge of the repertoire of self-peptides naturally presented by H2-M3 and show that this MHC class I molecule can present short endogenous peptide ligands; and 3) suggest that mitochondrial DNA mutations that modify the repertoire of H2-M3-associated mitochondrial peptides are representative of mitochondrial DNA mutations in general.
Recombinant IL-10 and IL-10/Fc treatment down-regulate egg antigen-specific delayed hypersensitivity reactions and egg granuloma formation in schistosomiasis.
Authors: Flores-Villanueva P O , Zheng X X , Strom T B , Stadecker M J 
Published: December 2022

Abstract
In infection with the helminth Schistosoma mansoni, parasite eggs elicit a Th cell-mediated hepatic granulomatous inflammation that leads to scarring, portal hypertension, hemorrhage, and death. On the other hand, the cytokine IL-10 has been shown to decrease egg Ag-specific Th cell responses by down-regulating MHC class II as well as B7 costimulatory molecule expression on accessory cells. We now test the effect of IL-10 in vivo on models of egg Ag-specific hypersensitivity as well as on the natural disease. Systemic administration of IL-10 significantly inhibited delayed-type hypersensitivity reactions to egg Ag as well as primary and secondary granuloma formation to eggs embolized in the lung. However, significant inhibition of hepatic granuloma formation associated with the natural infection required the use of an IL-10/Fc fusion protein with a prolonged in vivo half-life. Lymph node cells from IL-10/Fc-treated mice produced less IL-2 and IFN-gamma, and more IL-4 and IL-10 than control cells, suggesting that reduced egg granuloma formation resulted primarily from down-regulation of Th1 responses. These results indicate that suitable administration of exogenous IL-10 can be effective in ameliorating immunopathologic damage associated with schistosomiasis.
Liver NK1.1+ CD4+ alpha beta T cells activated by IL-12 as a major effector in inhibition of experimental tumor metastasis.
Authors: Takeda K , Seki S , Ogasawara K , Anzai R , Hashimoto W , Sugiura K , Takahashi M , Satoh M , Kumagai K 
Published: December 2022

Abstract
We demonstrate herein evidence that IL-12-activated alpha beta T cells with intermediate TCR (NK1+ TCRint cells) in the liver inhibit metastases in the lung as well as in the liver metastases of i-v. injected tumors. IL-12 administration enhanced NK1 expression of NK1+ TCRint cells (NK1high) and increased CD4 weakly positive (CD4low) TCRint cells, while both CD4+ TCRint cells and double-negative TCRint cells were proportionally diminished. Accordingly, the major parts of NK1high TCRint cells are CD4low cells, and most of these cells are V beta 8+ cells. The cytotoxic assays of IL-12-stimulated hepatic mononuclear cells after treatment with respective Abs and complement in vitro and after sorting revealed that CD4low NK1high TCRint cells are cytotoxic effectors. When IL-12-stimulated hepatic mononuclear cells (but not splenocytes) were transferred into tumor-preinjected mice, EL-4 cell metastases in the liver as well as 3LL cell metastases in the lung were inhibited. The antimetastasis of hepatic mononuclear cells transfer was abrogated by the depletion of NK1+ cells, CD3+ cells, or CD4+ cells but not CD8+ cells before transfer. Moreover, transfer of these cells of nude mice into tumor-preinjected mice also inhibited metastases in both organs. Although NK1+ TCRint cells are nearly absent in the hepatic vein blood, a significant proportion of NK1high TCRint cells appeared by IL-12 administration. These results demonstrate that IL-12-stimulated liver NK1high TCRint cells, including extrathymic ones, are major effectors against tumor metastasis and suggest that the cells migrate and inhibit lung metastases.