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)

cAMP mediated signaling may play a suppressive role in immune response. We previously found that the cAMP-elevators (CTx and 8-Br-cAMP) inhibited IL-12, IL-la, IL-6 gene expression, but increased the transcriptional levels of IL-10 and IL-1Ra in LPS-treated murine peritoneal macrophages. The present study examined a possible molecular mechanism involved in cAMP elevators-induced inhibition of IL-12 p40 expression in response to LPS. Our data demonstrated that cAMP elevators downregulated IL-12 p40 mRNA expression and IL-12 p70 production in murine peritoneal macrophages. Subsequent studies revealed that cAMP-elevators blocked phosphorylation of p38 MAPK, but did not affect the activity of NF-kappaB binding to IL-12 promoter (-136/-112). This is the first report that cAMP elevators inhibit LPS-induced IL-12 production by a mechanism that is associated, at least in part, with p38-dependent inhibition by cAMP signaling pathways.
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PMID:cAMP elevators inhibit LPS-induced IL-12 p40 expression by interfering with phosphorylation of p38 MAPK in murine peritoneal macrophages. 1252 91

The many specific, yet overlapping and redundant activities of individual cytokines have been the basis for current concepts of therapeutical intervention. Cytokines are powerful two-edged weapons that can trigger a cascade of reactions and may show activities that often go beyond the single highly specific property that it is hoped they possess. Nevertheless, it can be stated that our new, though burgeoning, understanding of the biological mechanisms governing cytokine actions is an important contribution to medical knowledge. The crucial role of the anti-inflammatory cytokine, interleukin (IL)-10, in regulating potential molecular pathway mediating injury and cell death has attracted paramount attention in recent years. In this respect, the mitogen-activated protein kinase (MAPK) components have emerged as potential signalling cascades that regulate a plethora of cell functions, including inflammation and cell death. The biochemistry and molecular biology of cytokine actions, particularly IL-10, explain some well known and sometimes also some of the more obscure clinical aspects of the evolution of diseases.
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PMID:Interleukin-10 and the regulation of mitogen-activated protein kinases: are these signalling modules targets for the anti-inflammatory action of this cytokine? 1253 24

Heat shock protein (HSP) 60 nonspecifically activates cells of the innate immune system. In the present study, we characterized the effects of human HSP60 maturation, cytokine release, and T cell-activating capacity of bone marrow-derived dendritic cells (DC). Furthermore, we analyzed HSP60-induced signal transduction in DC. HSP60 strongly stimulated DC for maturation and release of TNF-alpha, IL-12, and IL-1 beta. However, HSP60 elicited only a weak IL-10 response in DC suggesting a Th1 bias. HSP60-treated DC induced proliferation of allogeneic T cells. Again, a Th1 bias was noted in that cocultures of allogeneic T cells and HSP60-treated DC released IFN-gamma but only small amounts of IL-10 and no detectable IL-4. Signaling via Toll-like receptor 4 was involved in HSP60-induced cytokine release and maturation because DC of C3H/HeJ mice with a mutant Toll-like receptor 4 showed deficient response to HSP60. HSP60 was found to rapidly activate the mitogen-activated protein kinases p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase as well as I kappa B in DC. Phosphorylation of these signaling molecules was also mediated by LPS, but with much slower kinetics. Thus, HSP60 stimulates DC more rapidly than LPS and elicits a Th1-promoting phenotype. These results suggest that DC play a pivotal role in priming for destructive Th1-type responses at sites of local HSP60 release.
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PMID:Human heat shock protein 60 induces maturation of dendritic cells versus a Th1-promoting phenotype. 1259 56

H4/ICOS is a costimulatory molecule related to CD28. Its effects on early TCR signals have been analyzed in mouse CD4(+) Th2 cells, expressing H4/ICOS at higher levels than Th1 clones. Anti-H4/ICOS antibodies strongly enhanced CD3-mediated tyrosine phosphorylation of ZAP-70, zeta, or Vav, as well as extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 MAP kinase activation in these cells. The association of phosphoinositide 3-kinase (PI-3K) to H4/ICOS was enhanced by H4/ICOS cross-linking, and PI-3K inhibitors inhibited ERK and JNK activation and IL-4/IL-10 secretion, but not p38 MAP kinase or ZAP-70 activation. H4/ICOS-mediated activation of JNK, but not ERK or p38, is partially dependent on the expression of CD4 by the cells, whereas H4/ICOS costimulation is partially independent on CD28 expression. Cytochalasin D, an inhibitor of actin polymerization, inhibited ZAP-70, MAP kinase activation, or IL-4/IL-10 secretion. Neither cyclosporin A nor inhibitors of PKC produced detectable inhibition of ZAP-70 phosphorylation or MAP kinase activation in these Th2 cells. Cyclosporin A strongly inhibited IL-4, but not IL-10 secretion. ERK or JNKinhibitors partially inhibited IL-4 and IL-10 secretion, while PKC or p38 inhibitors had no significant effects on IL-4 or IL-10 secretion. Taken together, our data show clear similarities of costimulation mechanisms between H4/ICOS and CD28 during the early steps of TCR activation.
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PMID:Mechanisms of H4/ICOS costimulation: effects on proximal TCR signals and MAP kinase pathways. 1259 49

Despite its lack of specificity, the inhibitor SB 203580 has been widely used to implicate p38 mitogen-activated protein kinase (MAPK) in the synthesis of many cytokines. Here we show unequivocally that the production of interleukin (IL)-1beta, IL-6, IL-10, and tumor necrosis factor alpha (TNFalpha) requires p38 MAPK activity by demonstrating that the inhibitory effects of SB 203580 were reversed by expression of an SB 203580-resistant form of p38alpha (SBR-p38alpha) that fails to bind to SB 203580. This strategy established the requirement for p38 activity for the lipopolysaccharide-stimulated production of IL-10, IL-1beta, and IL-6 by the monocytic cell WEHI 274 and the production of IL-6 and TNFalpha stimulated by ligation of the Fc-gamma receptor of the mast cell MC/9. Expression of SBR-p38alpha in primary macrophages abrogated the ability of SB 203580 to inhibit the lipopolysaccharide-stimulated production of TNFalpha but not of IL-10. Expression of SBR-p38alpha in primary T lymphocytes abrogated the ability of SB 203580 to inhibit the production of interferon-gamma induced by co-ligation of CD3 and CD28 but not the production of interferon-gamma or IL-10 induced by IL-12. These results suggest that the levels of p38 MAPK activity required for maximal cytokine production vary with different cytokines and stimuli.
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PMID:Defining the involvement of p38alpha MAPK in the production of anti- and proinflammatory cytokines using an SB 203580-resistant form of the kinase. 1263 77

Schistosomiasis mansoni remains a significant public health problem in many parts of the tropics and subtropics. Clinical manifestations range from the asymptomatic intestinal form through to the hepatosplenic form of the disease, a potentially lethal clinical condition in a subsection of the exposed population. In this study, we investigated the mechanisms by which interleukin (IL)-10 production could be differentially controlled in patients with the intestinal and hepatosplenic forms of the disease, as IL-10 may play a fundamental role in the development of the hepatosplenic disease state. It is reported that p38 mitogen-activated protein (MAP) kinase signalling, and in particular p38 MAPK activation, is central to IL-10 production of cells from patients with schistosomiasis. Furthermore, the difference in the levels of activated p38 MAPK and the activation transcription factor (ATF-2), may explain the difference in the amount of IL-10 produced by cells from intestinal and hepatosplenic patients. We suggest that the type of immune response triggered in patients with hepatosplenomegaly could be influenced by the levels of phosphorylated p38 MAPK.
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PMID:P38 mitogen-activated protein kinase influence on the production of IL-10 in human schistosomiasis mansoni. 1265 92

Recently, we reported the cloning and preliminary characterization of a novel human immunomodulator named PLIF (placenta immunomodulatory ferritin). PLIF has a unique molecular structure, which is composed of a ferritin heavy chain-like domain and a novel cytokine-like domain called C48. Both intact molecule and C48 inhibit T cell proliferation following allogeneic or anti-CD3 stimuli. PLIF is localized at the fetal-maternal interface of human placenta and might play a role in down-modulating the maternal immune reaction toward the embryo. The inhibitory effect of PLIF on T cell activation can be direct, indirect through cytokine mediators, or both. In the present study we investigated the possible indirect effects of PLIF by using its bioactive domain C48. Measurement of various cytokines revealed that C48, predominantly, induce pronounced and rapid IL-10 production in monocytes, which is immune activation-independent. Further, we discovered that C48-induced IL-10 production is mediated through a calcium/calmodulin-p38 mitogen-activated protein (MAP) kinase signaling pathway. However, extracellular signal-related kinases1,2 (ERK1,2), also activated by C48 stimulation, exhibited a limiting effect on IL-10 production.
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PMID:PLIF induces IL-10 production in monocytes: a calmodulin-p38 mitogen-activated protein kinase-dependent pathway. 1267 Aug 72

CC chemokine receptor 1 (CCR1) has been implicated in inflammation. The present study examined the signaling mechanisms that mediate GM-CSF/IL-10-induced synergistic CCR1 protein expression in monocytic U937 cells. GM-CSF alone markedly increased both the mRNA and protein expression of CCR1. IL-10 augmented GM-CSF-induced CCR1 protein expression with no effect on mRNA expression. PD098059 and U0126 (two MEK inhibitors), and LY294002 (a PI3K inhibitor) inhibited GM-CSF/IL-10-induced CCR1 gene and protein expression. PD098059, U0126, and LY294002 also attenuated chemotaxis of GM-CSF/IL-10-primed U937 cells in response to MIP-1alpha. Immunoblotting studies show that GM-CSF alone induced ERK2 phosphorylation; whereas, IL-10 alone induced p70(S6k) phosphorylation in U937 cells. Neither cytokine when used alone induced PKB/Akt phosphorylation. Combined GM-CSF/IL-10 treatment of U937 cells induced phosphorylation of ERK2, p70(S6k), and PKB/Akt. PD098059 and U0126 completely abrogated ERK2 phosphorylation; whereas, LY294002 completely blocked PKB/Akt and p70(S6k) phosphorylation. Our findings indicate that IL-10 may potentiate GM-CSF-induced CCR1 protein expression in U937 cells via activation of PKB/Akt and p70(S6k).
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PMID:IL-10 synergistically enhances GM-CSF-induced CCR1 expression in myelomonocytic cells. 1271 32

The purposes of this study was to determine the effects of recombinant human interleukin-10 (rhIL-10) on proliferation of vascular smooth muscle cells (VSMCs) stimulated by advanced glycation end products (AGE) and neointima hyperplasia after rat carotid arterial injury. Rat aortic VSMCs were cultured and treated with rhIL-10 or AGE respectively, and then co-treated with rhIL-10 and AGE. Proliferation of VSMCs was quantified by colormetric assay. Cell cycle analysis was performed by flow cytomertry. Sprague-Dawley rats were treated with recombinant human IL-10 (rhIL-10) for 3 d after carotid arteries injury. The ratio of neointima to media area at the site of arterial injury was measured 28 d after balloon injury. The p44/42 MAPK activity was evaluated by the immunoblotting technique using anti-p44/42 phospho-MAPK antibody. Compared to control, AGE stimulated VSMCs proliferation. rhIL-10 alone had no effect on VSMCs growth. With AGE stimulation, rhIL-10, at dose as low as 10 ng/ml, inhibited VSMCs growth (P<0.05). The cell number in G(0)/G(1) phase of AGE and rhIL-10 co-treatment group was higher than that of AGE treatment alone (P<0.01) by flow cytometry analysis. Compared with the control group of neointima hyperplasia in rats, the ratio of neointima to media area of recombinant human IL-10 group was reduced by 45% (P<0.01). The p44/42 MAPK activity was significantly enhanced by AGE. The AGE effects were opposed by rhIL-10. The anti-inflammatory cytokine rhIL-10 inhibits AGE-induced VSMCs proliferation. Recombinant human IL-10 also inhibited neointima hyperplasia after carotid artery injury in rats. The results suggest the possibility that recombinant human IL-10, as a potential therapeutic approach, prevents neointimal hyperplasia.
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PMID:Recombinant human interleukin-10 inhibits proliferation of vascular smooth muscle cells stimulated by advanced glycation end products and neointima hyperplasia after carotid injury in the rat. 1271 99

Cyclic AMP is a very important regulator in a wide range of biological processes, including inflammatory reactions. To investigate the role of cAMP in microglia, we examined the effect of dibutyryl-cAMP (dbcAMP) on lipopolysaccharide (LPS)-stimulated cytokine expression and signaling pathways in murine BV2 microglial cells. DbcAMP strongly suppressed LPS-induced TNF-alpha expression, without affecting NO, IL-6 or TGF-beta1 expression. In contrast, LPS-induced IL-1beta or IL-10 expressions were dramatically increased by dbcAMP. We further examined the effect of elevated cAMP on signaling molecules such as MAP kinases (p38 MAPK, ERK and JNK), NF-kappaB and AP1, which are involved in the regulation of inflammatory responses. DbcAMP decreased the LPS-induced phosphorylation of p38 MAPK, while it modestly enhanced the ERK activity. JNK phosphorylation was slightly reduced by dbcAMP only at the later time point. Electrophoretic mobility shift assay revealed that the elevated cAMP potentiated AP-1 binding activity by enhancing c-fos binding. On the other hand, dbcAMP repressed NF-kappaB-mediated transcription without affecting NF-kappaB binding. Treatment with H89, a selective inhibitor of protein kinase A, completely reversed cAMP-induced IL-10 and IL-1beta upregulation but only partially reversed the cAMP-induced repression of TNF-alpha. Thus, the effect of dbcAMP in BV2 cells appears to be mediated through both protein kinase A-dependent and -independent pathways. Taken together, our results demonstrate that cAMP modulates microglia activation in a diverse and complex manner.
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PMID:Selective modulation of lipopolysaccharide-stimulated cytokine expression and mitogen-activated protein kinase pathways by dibutyryl-cAMP in BV2 microglial cells. 1275 10


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