Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T cell proliferation and cytokine production usually require stimulation via both the TCR/CD3 complex and the CD28 costimulatory receptor. Using purified human CD4+ peripheral blood T cells, we show that CD28 stimulation alone activates p38 alpha mitogen-activated protein kinase (p38 alpha). Cell proliferation induced by CD28 stimulation alone, a response attributed to CD4+CD45RO+ memory T cells, was blocked by the highly specific p38 inhibitors SB 203580 (IC50 = 10-80 nM) and RWJ 67657 (IC50 = 0.5-4 nM). In contrast, proliferation induced by anti-CD3 plus anti-CD28 mAbs was not blocked. Inhibitors of p38 also blocked CD4+ T cell production of IL-4 (SB 203580 IC50 = 20-100 nM), but not IL-2, in response to CD3 and CD28 stimulation. IL-5, TNF-alpha, and IFN-gamma production were also inhibited, but to a lesser degree than IL-4. IL-4 production was attributed to CD4+CD45RO+ T cells, and its induction was suppressed by p38 inhibitors at the mRNA level. In polarized Th1 and Th2 cell lines, SB 203580 strongly inhibited IL-4 production by Th2 cells (IC50 = 10-80 nM), but only partially inhibited IFN-gamma and IL-2 production by Th1 cells (<50% inhibition at 1 microM). In both Th1 and Th2 cells, CD28 signaling activated p38 alpha and was required for cytokine production. These results show that p38 alpha plays an important role in some, but not all, CD28-dependent cellular responses. Its preferential involvement in IL-4 production by CD4+CD45RO+ T cells and Th2 effector cells suggests that p38 alpha may be important in the generation of Th2-type responses in humans.
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PMID:p38 alpha mitogen-activated protein kinase is activated by CD28-mediated signaling and is required for IL-4 production by human CD4+CD45RO+ T cells and Th2 effector cells. 1035 55

Triggering of CD4 coreceptors on both human and murine T cells can suppress TCR/CD3-induced secretion of IL-2. We show here that pretreatment of murine CD4+ T cells with the CD4-specific mAb YTS177 inhibits the CD3-mediated activation of the IL-2 promoter factors NF-AT and AP-1. Ligation of CD4 molecules on T cells leads to a transient stimulation of extracellular signal-regulated kinase (Erk) 2, but not c-Jun N-terminal kinase (JNK) activity. Pretreatment with anti-CD4 mAb impaired anti-CD3-induced Erk2 activation. Costimulation with anti-CD28 overcame the inhibitory effect of anti-CD4 Abs, by induction of JNK activation. The in vivo relevance of these studies was demonstrated by the observation that CD4+ T cells from BALB/c mice injected with nondepleting anti-CD4 mAb were inhibited in their ability to respond to OVA Ag-induced proliferation and IL-2 secretion. Interestingly, in vivo stimulation with anti-CD28 mAb restored IL-2 secretion. Furthermore, animals pretreated with anti-CD4 elicited enhanced IL-4 secretion induced by OVA and CD28. These observations suggest that CD4-specific Abs can inhibit T cell activation by interfering with signal 1 transduced through the TCR, but potentiate those delivered through the costimulatory molecule CD28. These studies have relevance to understanding the mechanism of tolerance induced by nondepleting anti-CD4 mAb used in animal models for allograft studies, autoimmune pathologies, and for immunosuppressive therapies in humans.
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PMID:CD4-mediated signals induce T cell dysfunction in vivo. 1039 53

CD28 costimulation amplifies TCR-dependent signaling in activated T cells, however, the biochemical mechanism(s) by which this occurs is not precisely understood. The small GTPase Rac-1 controls the catalytic activity of the mitogen-activated protein kinases (MAPKs) and cell cycle progression through G1. Rac-1 activation requires the phospho-tyrosine (p-Tyr)-dependent recruitment of the Vav GDP releasing factor (GRF) to the plasma membrane and assembly of GTPase/GRF complexes, an event critical for Ag receptor-triggered T cell activation. Here, we show that TCR/CD28 costimulation synergistically induces Rac-1 GDP/GTP exchange. Our findings, obtained by using ZAP-70-negative Jurkat T cells, indicate that CD28 costimulation augments TCR-mediated T cell activation by increasing the ZAP-70-mediated Tyr phosphorylation of Vav. This event regulates the Rac-1-associated GTP/GDP exchange activity of Vav and downstream pathway(s) leading to PAK-1 and p38 MAPK activation. CD28 amplifies TCR-induced ZAP-70 activity and association of Vav with ZAP-70 and linker for activation of T cells (LAT). These results favor a model in which ZAP-70 regulates the intersection of the TCR and CD28 signaling pathways, which elicits the coupling of TCR and CD28 to the Rac-1, PAK-1, and p38 MAPK effector molecules.
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PMID:TCR and CD28 are coupled via ZAP-70 to the activation of the Vav/Rac-1-/PAK-1/p38 MAPK signaling pathway. 1039 78

Activation-induced cell death of T cells typically occurs late in the primary response after a prior proliferative response. Here, we describe a novel form of cell death in which purified naive murine CD4+ cells undergo apoptosis within 18 h in vitro after strong TCR ligation. Such rapid-onset TCR-mediated death of T cells does not involve cell division and is Fas-dependent, inhibited by CD28 (and IL-6) costimulation and enhanced by IL-4 and IL-7; by contrast, spontaneous death of CD4+ cells cultured alone is Fas-independent and inhibited by IL-4 and IL-7. TCR-mediated Fas-dependent death of CD4+ cells is prevented by combined TCR/Fas ligation and by drugs that inhibit calcineurin-dependent signaling and mitogen-activated protein kinase MEK1 activation.
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PMID:Strong TCR ligation without costimulation causes rapid onset of Fas-dependent apoptosis of naive murine CD4+ T cells. 1043 14

The effect of CD3-CD4 coligation on CD3-mediated activation of normal mouse CD4(+) T lymphocytes has been analyzed in the absence of exogenous lymphokines. If anti-CD3 and anti-CD4 antibodies are adsorbed to culture wells by means of previously adsorbed anti-Ig antibodies (indirect binding), CD3-CD4 coligation inhibits activation measured as cell proliferation or as secretion of IL-2, IL-4, and IFN-gamma. Addition of IL-2, anti-CD28 antibodies, or phorbol esters, but not IL-1, IL-4, or ionomycin, blocked CD4-mediated inhibition and restored the response to levels equal or higher than those of cultures activated by anti-CD3 alone. In contrast, CD3-CD4 coligation by antibodies directly adsorbed to culture wells potentiated anti-CD3-induced activation, either in the absence or in the presence of exogenous costimuli. Similar results were observed when CD4(+) T cells of naive phenotype (CD44(low), CD45RB(high)) were used in the experiments. The analysis of early tyrosine phosphorylation in CD4(+) T cells shows that phosphorylation of many cell substrates is clearly enhanced upon CD3-CD4 coligation using indirectly or directly bound antibodies, yet certain substrates are mainly phosphorylated under inhibitory conditions. Although CD28 ligation does not produce any clear change in the tyrosine phosphorylation pattern in lysates from cells activated by indirectly bound anti-CD3 plus anti-CD4 antibodies, the analysis of active forms of the MAP kinase ERK suggests that downstream signaling pathways involved in IL-2 gene activation can be differentially activated depending on the direct or indirect CD3-CD4 adsorption and CD28 ligation.
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PMID:Antibody-induced CD3-CD4 coligation inhibits TCR/CD3 activation in the absence of costimulatory signals in normal mouse CD4(+) T lymphocytes. 1044 9

4-1BB is a member of the TNFR superfamily expressed on activated CD4+ and CD8+ T cells. 4-1BB can costimulate IL-2 production by resting primary T cells independently of CD28 ligation. In this study, we report signaling events following 4-1BB receptor aggregation using an Ak-restricted costimulation-dependent T cell hybridoma, C8.A3. Aggregation of 4-1BB on the surface of C8.A3 cells induces TNFR-associated factor 2 recruitment, which in turn recruits and activates apoptosis signal-regulating kinase-1, leading to downstream activation of c-Jun N-terminal/stress-activated protein kinases (JNK/SAPK). 4-1BB ligation also enhances anti-CD3-induced JNK/SAPK activation in primary T cells. Overexpression of a catalytically inactive form of apoptosis signal-regulating kinase-1 in C8.A3 T cells interferes with activation of the SAPK cascade and with IL-2 secretion, consistent with a critical role for JNK/SAPK activation in 4-1BB-dependent IL-2 production. Given the ability of both CD28 and 4-1BB to induce JNK/SAPK activation, we asked whether hyperosmotic shock, another inducer of this cascade, could function to provide a costimulatory signal to T cells. Osmotic shock of resting primary T cells in conjunction with anti-CD3 treatment was found to costimulate IL-2 production by the T cells, consistent with a pivotal role for JNK/SAPK in T cell costimulation.
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PMID:Role of the stress kinase pathway in signaling via the T cell costimulatory receptor 4-1BB. 1047 61

On the basis of recent reports we discuss the role of Vav in TCR-dependent signaling pathways. The Vav protein is GDP/GTP exchange factor for Rac, which initiates transduction of signals in JNK pathway. Upon stimulation of TCR by antigenic peptides, Vav associates with Zap-70 in TCR/CD3 signaling complex and becomes phosphorylated on Tyr-174 by tyrosine kinase Lck. The function of Vav is modulated by substrates and products of PI3-kinase activated by interaction of CD28 on thymocytes with B7 on antigen presenting cells. The PI3-kinase substrates inhibit activation of Vav, while the products enhance phosphorylation and activation of Vav by Lck. It seems that Vav functions in key point of TCR-mediated signaling pathway, which is regulated by costimulatory molecule (CD28) necessary for negative selection. The Vav-mediated integration of signals results in positive or negative selection of thymocytes.
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PMID:[The role of vav protein in TCR-mediated signaling with MHC/peptide complexes leading to positive or negative selection of thymocytes]. 1054 57

c-Jun N-terminal kinase (JNK) is activated when T-lymphocytes are stimulated jointly through the T-cell receptor (TCR) and CD28, and it contributes to T-cell activation and IL-2 production through phosphorylation of transcription factors, including c-Jun. We performed in vitro kinase assays on JNK in CD4(+) T-cells, from young and old mice, activated by antibodies to CD3, CD4, and CD28, and found a approximately 2-fold decline in JNK activity at the peak of activation, but no significant change in the kinetics of stimulation or in the steady-state expression of JNK. We found a similar decline in c-Jun phosphorylation in stimulated CD4(+) T-cells from old mice, suggesting that JNK activation also declined with age in intact cells. Aging does not, however, alter the level of Ras activation by anti-CD3/CD4 +/- anti-CD28 or change the level of Ras protein in CD4(+) cells, suggesting that the JNK defect is due to changes in the regulation of other upstream regulators. Our results suggest that a decline with age in JNK responses may contribute to the decline in proliferation and IL-2 production seen in CD4(+) T-cells from old mice.
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PMID:Age-related decline in activation of JNK by TCR- and CD28-mediated signals in murine T-lymphocytes. 1060 24

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

The c-Jun NH(2)-terminal kinases (JNKs) are a group of mitogen-activated protein (MAP) kinases that participate in signal transduction events mediating specific cellular functions. Activation of JNK is regulated by phosphorylation in response to cellular stress and inflammatory cytokines. Here, we demonstrate that JNK is regulated by a second, novel mechanism. Induction of Jnk gene expression is required in specific tissues before activation of this signaling pathway. The in vivo and in vitro ligation of the T cell receptor (TCR) leads to induction of JNK gene and protein expression. TCR signals are sufficient to induce JNK expression, whereas JNK phosphorylation also requires CD28-mediated costimulatory signals. Therefore, both expression and activation contribute to the regulation of the JNK pathway to ensure proper control during the course of an immune response.
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PMID:Regulation of c-Jun NH(2)-terminal kinase (Jnk) gene expression during T cell activation. 1062 Jun 12


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