Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-Jun N-terminal kinase (JNK) can be activated in T-cells either by the combination of TCR and CD28 costimulation or by a variety of stress-related stimuli including UV light, H(2)O(2), and hyperosmolar sorbitol solutions. In T-lymphocytes, TCR/CD28 stimulation of JNK leads to induction of new gene expression via c-Jun, ATF-2, and Elk-1. Phosphorylation of c-Jun in CD4(+) T-cells stimulated by CD3/CD4/CD28 cross-linking declines with age, due to diminished activation of JNK. Here we show that the age-related decline in TCR/CD28 activation of JNK reflects two effects of age: the accumulation of memory cells (in which JNK stimulation is poor regardless of donor age) and age-dependent declines in JNK activation within the naive subset. Cyclosporin A inhibits induction of JNK function by TCR/CD28, PMA/ionomycin, ceramide, or H(2)O(2), but not induction by UV light or hyperosmolar sorbitol. Although aging impairs JNK induction by UV light, it has no effect on JNK activation by ceramide, H(2)O(2), or sorbitol. The data as a whole indicate that there are at least four pathways that activate JNK in CD4(+) T-cells, of which two are age-sensitive and two others unaffected by aging. Two of the pathways (UV and hyperosmolar sorbitol) are insensitive to cyclosporin inhibition. Finally, we show that the alterations in JNK function are not due to changes in the expression of MKK4, an upstream activator of JNK, and that another JNK kinase, MKK7, is not expressed in splenic T-cells.
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PMID:Age-sensitive and -insensitive pathways leading to JNK activation in mouse CD4(+) T-cells. 1060 25

We have recently described the novel A6H antigen expressed on human peripheral blood T cells and on renal cell carcinoma cells. Cross-linking of the A6H antigen results in co-stimulation of human CD4(+) T cells, characterized by induction of the transcription factor activator protein-1 (AP-1), proliferation and prominent IFN-gamma production, but low levels of IL-2. The proximal signaling events associated with A6H ligation include protein tyrosine kinase phosphorylation and association of p56 Lck, ZAP-70 and the TCR zeta chain. In this study we show that A6H co-stimulation selectively induced activation of the p38 mitogen-activated protein kinase (MAPK) pathway, whereas no significant c-Jun N-terminal kinases (JNK) activity was observed. In contrast, CD28 co-stimulation resulted in both p38 and JNK MAPK activities. Human CD4(+) T cells co-stimulated with A6H up-regulated AP-1 binding proteins reactive with a proximal AP-1 binding site in the human IFN-gamma promoter and a consensus AP-1 binding site. Moreover, preincubation of the T cells with the specific p38 MAPK inhibitor SB203580 resulted in decreased AP-1 binding following A6H or CD28 co-stimulation. This suggests that the p38 MAPK pathway is required for induction of full AP-1 binding activity in human CD4(+) T cells co-stimulated with A6H or CD28. Blocking the p38 MAPK pathway by SB203580 completely inhibited IFN-gamma production from A6H co-stimulated T cells and radically reduced IFN-gamma production from T cells co-stimulated with anti-CD28. In contrast, no significant inhibition of IL-2 production was seen after blocking of the p38 MAPK in either A6H or CD28 co-stimulated T cells. Since the p38 MAPK recently has been shown to be critically involved in regulation of IFN-gamma production from T(h)1 cells, we propose that A6H co-stimulation induces a specific pathway, mediated via p38 and AP-1 activation, for induction of a T(h)1 profile in human CD4(+) T cells.
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PMID:Selective induction of p38 mitogen-activated protein kinase activity following A6H co-stimulation in primary human CD4(+) T cells. 1070 Apr 60

To delineate the molecular mechanisms regulating Th2 cell differentiation, CD28-mediated generation of Th2 effectors was analyzed. In the absence of TCR ligation CD28 stimulation induced Th2 differentiation of memory but not of naive CD4(+) T cells, whereas costimulation via CD28 and the TCR enhanced Th2 differentiation from naive T cells but suppressed it from memory T cells. Stimulation of T cells via the CD28 pathway, therefore, provided critical signals facilitating Th2 cell differentiation. By comparing the responses to CD28 stimulation in memory and naive T cells and by using specific inhibitors, signaling pathways were defined that contributed to Th2 differentiation. CD28-induced Th2 differentiation required IL-4 stimulation and the activation of the mitogen-activated protein kinases p38 and extracellular signal-regulated kinases 1/2. CD28 engagement directly initiated IL-4 gene transcription in memory T cells and induced activation of phosphatidylinositol 3-kinase, p38, and c-Jun NH(2)-terminal kinase/stress-activated protein kinase pathways. Extracellular signal-regulated kinase phosphorylation that was necessary for Th2 differentiation, however, required stimulation by IL-2. These results indicate that optimal TCR-independent generation of Th2 effectors requires coordinate signaling via the CD28 and IL-2 pathways. TCR-independent generation of Th2 effectors might provide a mechanism to control Th1-dominated cellular inflammation.
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PMID:Antigen-independent Th2 cell differentiation by stimulation of CD28: regulation via IL-4 gene expression and mitogen-activated protein kinase activation. 1125 80

The molecular basis of X-linked lymphoproliferative (XLP) disease has been attributed to mutations in the signaling lymphocytic activation molecule-associated protein (SAP), an src homology 2 domain-containing intracellular signaling molecule known to interact with the lymphocyte-activating surface receptors signaling lymphocytic activation molecule and 2B4. To investigate the effect of SAP defects on TCR signal transduction, herpesvirus saimiri-immortalized CD4 Th cells from XLP patients and normal healthy individuals were examined for their response to TCR stimulation. CD4 T cells of XLP patients displayed elevated levels of tyrosine phosphorylation compared with CD4 T cells from healthy individuals. In addition, downstream serine/threonine kinases are constitutively active in CD4 T cells of XLP patients. In contrast, TCR-mediated activation of Akt, c-Jun-NH(2)-terminal kinases, and extracellular signal-regulated kinases in XLP CD4 T cells was transient and rapidly diminished when compared with that in control CD4 T cells. Consequently, XLP CD4 T cells exhibited severe defects in up-regulation of IL-2 and IFN-gamma cytokine production upon TCR stimulation and in MLRs. Finally, SAP specifically interacted with a 75-kDa tyrosine-phosphorylated protein upon TCR stimulation. These results demonstrate that CD4 T cells from XLP patients exhibit aberrant TCR signal transduction and that the defect in SAP function is likely responsible for this phenotype.
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PMID:Abnormal T cell receptor signal transduction of CD4 Th cells in X-linked lymphoproliferative syndrome. 1150 8

Jun N-terminal kinase (JNK) is a stress-activated protein kinase that can be induced by inflammatory cytokines, bacterial endotoxin, osmotic shock, UV radiation, and hypoxia. We report the identification of an anthrapyrazolone series with significant inhibition of JNK1, -2, and -3 (K(i) = 0.19 microM). SP600125 is a reversible ATP-competitive inhibitor with >20-fold selectivity vs. a range of kinases and enzymes tested. In cells, SP600125 dose dependently inhibited the phosphorylation of c-Jun, the expression of inflammatory genes COX-2, IL-2, IFN-gamma, TNF-alpha, and prevented the activation and differentiation of primary human CD4 cell cultures. In animal studies, SP600125 blocked (bacterial) lipopolysaccharide-induced expression of tumor necrosis factor-alpha and inhibited anti-CD3-induced apoptosis of CD4(+) CD8(+) thymocytes. Our study supports targeting JNK as an important strategy in inflammatory disease, apoptotic cell death, and cancer.
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PMID:SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. 1171 29

The recruitment of Ag-specific T cells to sites of inflammation is a crucial step in immune surveillance. Although the molecular interactions controlling T cell extravasation are relatively well characterized, the effects of these events on T cell function are still poorly understood. Using an in vitro model of transendothelial migration of human CD4(+) memory T cells, we have investigated the molecular and functional changes induced in T cells that come into contact with the endothelium. First, we show that transendothelial migration is precluded by signals that lead to T cell division. In addition, activation of the transcription factor AP-1, without induction of NF-kappaB, is observed in T cells after noncognate interactions with endothelial cells (EC), a pattern of transcriptional regulation different from that observed in dividing T cells. Up-regulation of certain adhesion (CD11a, CD49d), activation (CD69), and costimulatory (CD86) receptors accompany these transcriptional events. Most importantly, recently migrated T cells display a faster rate of migration when reseeded onto an EC monolayer. Finally, T cells become hyperresponsive to antigenic challenge after noncognate interactions with the endothelium. These effects appear not to be due to the selection of preactivated T lymphocytes, because they occur also in clonal T cell populations and appear to be mediated by alpha(L)beta(2) integrin-CD54 interactions. We conclude that CD4(+) memory T cell extravasation is accompanied by phenotypic and functional changes induced by the interactions with the EC, which favor tissue infiltration by T cells and their further activation once they reach the antigenic site.
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PMID:Functional consequences of noncognate interactions between CD4+ memory T lymphocytes and the endothelium. 1190 76

The c-Jun NH(2)-terminal kinase (JNK) signaling pathway is induced by cytokines and stress stimuli and is implicated in cell death and differentiation, but the specific function of this pathway depends on the cell type. Here we examined the role of JNK1 and JNK2 in CD8(+) T cells. Unlike CD4(+) T cells, the absence of JNK2 causes increased interleukin (IL)-2 production and proliferation of CD8(+) T cells. In contrast, JNK1-deficient CD8(+) T cells are unable to undergo antigen-stimulated expansion in vitro, even in the presence of exogenous IL-2. The hypoproliferation of these cells is associated with impaired IL-2 receptor alpha chain (CD25) gene and cell surface expression. The reduced level of nuclear activating protein 1 (AP-1) complexes in activated JNK1-deficient CD8(+) T cells can account for the impaired IL-2 receptor alpha chain gene expression. Thus, JNK1 and JNK2 play different roles during CD8(+) T cell activation and these roles differ from those in CD4(+) T cells.
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PMID:c-Jun NH(2)-terminal kinase (JNK)1 and JNK2 have distinct roles in CD8(+) T cell activation. 1192 26

The structurally related neuropeptides VIP and PACAP are released within the lymphoid organs following antigenic stimulation, and modulate the function of inflammatory cells through specific receptors. In activated macrophages, VIP and PACAP inhibit the production of pro-inflammatory agents (cytokines, chemokines, and nitric oxide), and stimulate the production of the anti-inflammatory cytokine IL-10. These events are mediated through the VIP/PACAP effects on de novo expression or nuclear translocation of several transcription factors, i.e., NFkappaB, CREB, c-Jun, JunB, and IRF-1. The in vivo administration of VIP/PACAP results in a similar pattern of cytokine and chemokine modulation, which presumably mediates the protective effect of VIP/PACAP in septic shock. In addition, VIP/PACAP reduce the expression of the co-stimulatory molecules B7.1/B7.2, and the subsequent stimulatory activity of macrophages for T-helper cells. In T-cells expressing specific VIP/PACAP receptors, VIP and PACAP inhibit the expression of FasL through effects on NFkappaB, NFAT, and Egr2/3. The reduction of FasL expression has several biological consequences: inhibition of antigen-induced cell death in CD4 T-cells, inhibition of the FasL-mediated cytotoxicity of CD8 and CD4 effectors against direct and bystander targets, and promotion of long-term memory Th2 cells, through a positive effect on the survival of Th2, but not Th1, effectors. The various biological effects of VIP and PACAP are discussed within the range of a general anti-inflammatory model.
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PMID:Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as modulators of both innate and adaptive immunity. 1209 Apr 63

Activation of CD4(+) T cells is governed by interplay between stimulatory and inhibitory receptors; predominance of stimulatory signals favors autoimmune reactions. In patients with rheumatoid arthritis, expression of the critical costimulatory molecule, CD28, is frequently lost. Instead, CD4(+)CD28(null) T cells express killer immunoglobulin-like receptors (KIRs) with a preferential expression of the stimulatory receptor, CD158j. The frequency of CD4(+)CD28(null) T cells in rheumatoid arthritis (RA) correlates with the risk for more severe disease. Moreover, the KIR2DS2 gene, which encodes for CD158j, is a genetic risk factor for rheumatoid vasculitis. CD158j signals through the adaptor molecule, KARAP/DAP12, to positively regulate cytotoxic activity in NK cells. However, the majority of CD4(+)CD28(null) T cell clones lacked the expression of KARAP/DAP12. Despite the absence of KARAP/DAP12, CD158j was functional and augmented interferon-gamma production after T cell receptor stimulation. Cross-linking of CD158j resulted in selective phosphorylation of c-Jun NH(2)-terminal protein kinase (JNK) and its upstream kinase, MKK4 that led to the expression of ATF-2 and c-Jun, all in the absence of extracellular signal-regulated kinase (ERK)1/2 phosphorylation. Mutation of the lysine residue within the transmembrane domain of CD158j abolished JNK activation, suggesting that an alternate adaptor molecule was being used. CD4(+)CD28(null) T cells expressed DAP10 and inhibition of phosphatidylinositol 3-kinase, which acts downstream of DAP10, inhibited JNK activation; however, no interaction of DAP10 with CD158j could be detected. Our data suggest that CD158j in T cells functions as a costimulatory molecule through the JNK pathway independent of KARAP/DAP12 and DAP10. Costimulation by CD158j may contribute to the autoreactivity of CD4(+)CD28(null) T cells in RA.
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PMID:Selective activation of the c-Jun NH2-terminal protein kinase signaling pathway by stimulatory KIR in the absence of KARAP/DAP12 in CD4+ T cells. 1259 2

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors expressed in a wide variety of cells. Our studies and others have demonstrated that both human and murine T cells express PPARgamma and that expression can be augmented over time in mitogen-activated splenocytes. PPARgamma ligands decrease proliferation and IL-2 production, and induce apoptosis in both B and T cells. PPARgamma ligands have also been shown to be anti-inflammatory in multiple models of inflammatory disease. In the following study, we demonstrate for the first time that PPARgamma is expressed in both murine CD4 and CD8 cells and that PPARgamma ligands directly decrease IFN-gamma expression by murine and transformed T cell lines. Unexpectedly, GW9662, a PPARgamma antagonist, increases lymphocyte IFN-gamma expression. Transient transfection studies reveal that PPARgamma ligands, in a PPARgamma-dependent manner, potently repress an IFN-gamma promoter construct. Repression localizes to the distal conserved sequence of the IFN-gamma promoter. Our studies also demonstrate that PPARgamma acts on the IFN-gamma promoter by interfering with c-Jun activation. These studies suggest that many of the observed anti-inflammatory effects of PPARgamma ligands may be related to direct inhibition of IFN-gamma by PPARgamma.
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PMID:Repression of IFN-gamma expression by peroxisome proliferator-activated receptor gamma. 1518 32


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