Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-1 (IL-1) induces the phosphorylation of Stat1 on serine 727 but not on tyrosine 701. Analyses of mutant I1A cells, which lack the IL-1 receptor-associated kinase (IRAK), and of I1A cells reconstituted with deletion mutants of IRAK show that the IL-1-mediated phosphorylation of Stat1 on serine requires the IRAK protein but not its kinase activity and does not involve phosphatidylinositol-3'-kinase (PI3K) or the mitogen-activated protein (MAP) kinases p38 or ERK. IRAK and Stat1 interact in vivo, and this interaction is increased in response to IL-1, suggesting that IRAK may serve to recruit the as yet unknown IL-1-induced Stat1 serine kinase. Chemical inhibitors or dominant-negative forms of signaling components required to activate NF-kappa B, ATF, or AP-1 in response to IL-1 do not affect the phosphorylation of Stat1 on serine. IL-1 and tumor necrosis factor (TNF) enhance the serine phosphorylation of Stat1 that occurs in response to interferon-gamma (IFN-gamma) and potentiate IFN-gamma-mediated, Stat1-driven gene expression, thus contributing to the synergistic activities of these proinflammatory cytokines.
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PMID:IRAK-dependent phosphorylation of Stat1 on serine 727 in response to interleukin-1 and effects on gene expression. 1285 30

The chemokine, mob-1, is involved in inflammatory and immune responses and may be an important mediator of the inflammatory response in the liver. Here, we investigated the upstream signal pathways that could be involved in the regulation of mob-1 expression. We have found that in primary rat hepatocytes the isolation and subsequent culture of these cells induced mob-1 expression. A similar induction of mob-1 mRNA was observed when the hepatocytes were stimulated with interferon-gamma (IFN-gamma). When hepatocytes were stimulated with IFN-gamma or cytokine mixture (IFN-gamma, interleukin-1beta and tumour necrosis factor-alpha), c-Jun N-terminal kinase (JNK), p38 and extracellular-regulated kinase (ERK) were phosphorylated, suggesting an involvement of the mitogen-activated protein kinases (MAPK) in the induction of mob-1 expression. The p38 kinase inhibitor, SB 203580, and the NF-kappaB inhibitor, MG-132, inhibited the induction of mob-1 mRNA and the effects were not additive. These results demonstrate that in primary rat hepatocytes the transient induction of mob-1 expression was regulated by p38 kinase and NF-kappaB through a common regulatory pathway.
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PMID:Regulation of the C-X-C chemokine, mob-1, gene expression in primary rat hepatocytes. 1290 69

Our previous study has shown that lipophilic 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors of statins can inhibit interferon-gamma-induced inducible nitric oxide synthase gene expression in RAW264.7 macrophages. In this study, we showed that lovastatin and fluvastatin are able to upregulate the mRNA expression of the suppressor of cytokine signaling-3 (SOCS-3) gene. This effect is specific for SOCS-3 and could be blocked by mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, while it was not affected by inhibitors of protein kinase C and A, mitogen-activated protein/extracellular signal-regulated kinase kinase, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, Src, Raf and Rho kinase. SOCS-3 expression results in the inhibition of interferon-gamma-, interleukin-6- and macrophage colony-stimulating factor-elicited signal transducer and activator of transcription phosphorylation, suggesting a novel anti-inflammatory mechanism of statins to down-modulate the functions of interferon-gamma-activated macrophages.
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PMID:Statins induce suppressor of cytokine signaling-3 in macrophages. 1464 48

Septic shock is the most common cause of death in intensive care units, and no effective treatment is available at present. Lipopolysaccharide (LPS) is the primary mediator of Gram-negative sepsis by inducing the production of macrophage-derived proinflammatory cytokines, in which activation of nuclear factor-kappaB (NF-kappaB) plays an important role. PC-SPES is an eight-herb mixture active against a variety of malignancies, including prostate cancer and leukemia. In this study, we demonstrated that PC-SPES inhibited the LPS-induced NF-kappaB reporter activity in RAW264.7 macrophages. Electrophoretic mobility shift assay showed that PC-SPES inhibited the binding of NF-kappaB to specific DNA sequences; however, it did not affect either degradation of inhibitory kappaBalpha or nuclear translocation of NF-kappaB. Also, we explored the effect of PCSPES on LPS-induced mitogen-activated protein (MAP) kinase signaling; PC-SPES did not affect LPS-induced phosphorylation of MAP kinases, including c-Jun NH2-terminal kinase, p38, and extracellular signal-regulated kinase 1/2. Moreover, PC-SPES decreased the production of proinflammatory cytokines and inducible enzymes, such as tumor necrosis factor (TNF) alpha, interleukin (IL)-1beta, IL-6, cyclooxygenase-2, as well as inducible nitric-oxide synthase in RAW264.7 macrophages and peritoneal macrophages from C57BL/6 mice after the cells were stimulated by either LPS or LPS and interferon-gamma. Furthermore, PC-SPES rescued C57BL/6 mice from death caused by LPS-induced septic shock in conjunction with decreased serum levels of TNFalpha and IL-1beta. Together, PC-SPES is a potent inhibitor of NF-kappaB and might be useful for the treatment of sepsis and inflammatory diseases.
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PMID:PC-SPES: a potent inhibitor of nuclear factor-kappa B rescues mice from lipopolysaccharide-induced septic shock. 1464 83

Osteopontin (OPN), also called cytokine Eta-1, expressed in the myocardium co-incident with heart failure plays an important role in post myocardial infarction (MI) remodeling by promoting collagen synthesis and accumulation. Angiotensin II (Ang II) and inflammatory cytokines are increased in the heart following MI. We studied the involvement of mitogen-activated protein kinases (ERK1/2, JNKs, p38 kinase) and reactive oxygen species (ROS) in Ang II- and cytokine-induced OPN gene expression in adult rat cardiac fibroblasts. Ang II alone increased OPN mRNA (3.3 +/- 0.3-folds; P < 0.05; n = 7), while interleukin-1beta (IL-1beta), tumor necrosis factor (TNF-alpha), and interferon-gamma (IFN-gamma) had no effect. A combination of Ang II with IL-1beta or TNF-alpha, not IFN-gamma, increased OPN mRNA more than Ang II alone. Nitric oxide donor, S-nitrosoacetylpenicillamine (SNAP), alone or in combination with Ang II had no effect. Diphenylene iodonium (DPI), inhibitor of NAD(P)H oxidase, and tiron, superoxide scavenger, inhibited Ang II- and Ang II+ IL-1beta-stimulated increases in OPN mRNA. Ang II activated ERK1/2 within 5 min of treatment, not JNKs. IL-1beta activated ERK1/2 and JNKs within 15 min of treatment. A combination of Ang II and IL-1beta activated ERK1/2 within 5 min of treatment. None of these stimuli activated p38 kinase. DPI almost completely inhibited Ang II + IL-1beta-stimulated activation of ERK1/2, while partially inhibiting JNKs. PD98059, ERK1/2 pathway inhibitor, and SP600125, JNKs inhibitor, partially inhibited Ang II + IL-1beta-stimulated increases in OPN mRNA. A combination of PD98059 and SP600125 almost completely inhibited Ang II + IL-1beta-stimulated increases in OPN mRNA. Thus, Ang II alone increases OPN expression, while IL-1beta and TNF-alpha act synergistically with Ang II to increase OPN mRNA possibly via NO independent mechanisms. The synergistic increase in OPN mRNA involves ROS-mediated activation of ERK1/2 and JNKs, not P38 kinase, pathways in cardiac fibroblasts.
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PMID:ERK1/2 and JNKs, but not p38 kinase, are involved in reactive oxygen species-mediated induction of osteopontin gene expression by angiotensin II and interleukin-1beta in adult rat cardiac fibroblasts. 1475 45

Given the important role of gaseous free radical nitric oxide (NO) in tumor cell biology, we investigated the ability of the anti-cancer drugs 5-Aza-2'-deoxycytidine (ADC) and paclitaxel to modulate NO production in mouse L929 fibrosarcoma cells. Both drugs reduced IFN-gamma-stimulated NO release in cultures of L929 and primary fibroblasts, but not in mouse peritoneal macrophages. The inhibitory effect was due to the reduced expression of inducible NO synthase (iNOS), the enzyme responsible for cytokine-induced intracellular NO synthesis, as both agents markedly suppressed the interferon-gamma (IFN-gamma)-triggered increase in iNOS concentration in L929 cells. In addition, ADC and paclitaxel prevented the IFN-gamma-triggered activation of p44/p42 mitogen-activated protein (MAP) kinase in L929 fibroblasts, suggesting a possible mechanism for the observed inhibition of iNOS expression. These results might have important implications for the therapeutic effect of ADC and paclitaxel, since their inhibitory action on NO release partly neutralized the NO-dependent toxicity of IFN-gamma on L929 fibrosarcoma cells.
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PMID:5-Aza-2'-deoxycytidine and paclitaxel inhibit inducible nitric oxide synthase activation in fibrosarcoma cells. 1475 26

We previously stated that interferon-gamma (IFN-gamma) is highly expressed in a transient and developmentally regulated manner by the trophectoderm of the pig blastocyst, which represents a monolayer of polarized epithelial cells, during early pregnancy. In order to study the molecular mechanisms of this atypical IFN-gamma gene expression, we established the pig trophectoderm cell line TBA B4-3. These cells develop a polarized phenotype with high transepithelial electrical resistance (TER) when grown on a microporous membrane. We previously showed that treatment of polarized TBA B4-3 cells with the strong protein kinase C (PKC) agonist phorbol 12-myristate-13-acetate (PMA) induced 3-4 days later a transient IFN-gamma mRNA expression and apical IFN-gamma protein secretion. In the present paper, we report that after PMA removal, a transient phase of p44/p42 mitogen-activated protein (MAP) kinase activation occurs, followed by a strong downregulation preceding the phase of IFN-gamma expression. Surprisingly, we found that inhibition of this surge of p44/p42 MAP kinase activation with MEK inhibitors (U0126 and PD98059) triggers earlier IFN-gamma mRNA and protein expression, correlated with earlier TER rising and restoration of epithelial phenotype. These results indicate that in the TBA B4-3 cell system, activation of this signaling pathway has a negative effect on IFN-gamma gene expression. These observations reinforce the hypothesis of a link between establishment of cell polarity and induction of IFN-gamma that could be mediated by signaling from intercellular junctions.
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PMID:IFN-gamma gene expression in epithelial trophectoderm cells is linked to downregulation of the p44/p42 MAP kinase pathway. 1498 82

In the CNS, astrocytes are significant sources of RANTES/CCL5 (regulated upon activation, normal T cell expressed and secreted), a CC-chemokine with important biological function. Astrocyte RANTES/CCL5 has been shown to be induced by interleukin-1 (IL-1), with interferon-gamma (IFNgamma) as a primer, but whether type I interferons play any role in the expression of RANTES/CCL5 is not known. In this report, we studied the detailed mechanism of RANTES/CCL5 induction in primary human astrocytes activated with IL-1 and IFNbeta. Ribonuclease protection assay and ELISA showed that IFNbeta, although not effective alone, increased IL-1-induced RANTES/CCL5 expression, but did not antagonize IFNgamma. IL-1 or IL-1/IFNbeta-induced RANTES/CCL5 expression was inhibited by the super-repressor IkappaBalpha or inhibitors of p38 or c-Jun N-terminal kinase (JNK) MAPKs (mitogen-activated protein kinases), but not by extracellular signal regulated kinases (ERK) inhibitors. IFNbeta enhanced IL-1-induced phosphorylation of p38 MAPK, but was not effective alone. Transfection with mutated RANTES/CCL5 promoter-reporter constructs revealed that kappaB, interferon-stimulated response element (ISRE) and CAATT-enhancer binding protein-beta (C/EBPbeta) sites all contributed to IL-1/IFNbeta-induced RANTES/CCL5 transcription. IFNbeta synergized with IL-1 to induce nuclear accumulation of C/EBPbeta protein. They also synergized to form nuclear ISRE complexes with Stat1, Stat2 and interferon regulatory factor-1 (IRF-1) proteins. Together, our results demonstrate that IFNbeta plays a positive regulatory role in the expression of RANTES/CCL5 in human astrocytes through several distinct mechanisms.
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PMID:Regulation of RANTES/CCL5 expression in human astrocytes by interleukin-1 and interferon-beta. 1522 86

In the present study, experiments were performed to explore the action of quercetin, the most widely distributed flavonoids, and its major metabolite, quercetin-3'-sulfate, on lipopolysaccharide (LPS)- and interferon-gamma (IFN-gamma)-induced nitric oxide (NO) production in BV-2 microglia. Quercetin could suppress LPS- and IFN-gamma-induced NO production and inducible nitric oxide synthase (iNOS) gene transcription, while quercetin-3'-sulfate had no effect. LPS-induced IkappaB kinase (IKK), nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1) activation, and IFN-gamma-induced NF-kappaB, signal transducer and activator of transcription-1 (STAT1) and interferon regulatory factor-1 (IRF-1) activation were reduced by quercetin. Moreover quercetin was able to induce heme oxygenase-1 expression. To address the involvement of heme oxygenase-1 induction in iNOS inhibition, heme oxygenase-1 antisense oligodeoxynucleotide was used. Quercetin-mediated inhibition of NO production and iNOS protein expression were partially reversed by heme oxygenase-1 antisense oligodeoxynucleotide, but was mimicked by hemin, a heme oxygenase-1 inducer. The involvement of signal pathways in quercetin-induced heme oxygenase-1 gene expression was associated with tyrosine kinase and mitogen-activated protein kinases activation. All these results suggest quercetin should provide therapeutic benefits for suppression of inflammatory-related neuronal injury in neurodegenerative diseases.
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PMID:Inhibition of iNOS gene expression by quercetin is mediated by the inhibition of IkappaB kinase, nuclear factor-kappa B and STAT1, and depends on heme oxygenase-1 induction in mouse BV-2 microglia. 1617 98

The molecular mechanisms for the anti-inflammatory activity of phenanthroindolizidine alkaloids were examined in an in vitro system mimicking acute inflammation by studying the suppression of lipopolysaccharide (LPS)/interferon-gamma (IFNgamma)-induced nitric oxide production in RAW264.7 cells. Two of the phenanthroindolizidine alkaloids, NSTP0G01 (tylophorine) and NSTP0G07 (ficuseptine-A), exhibited potent suppression of nitric oxide production and did not show significant cytotoxicity to the LPS/IFNgamma-stimulated RAW264.7 cells, in contrast to their respective cytotoxic effects on cancer cells. Tylophorine was studied further to investigate the responsible mechanisms. It was found to inhibit the induced protein levels of tumor necrosis factor-alpha, inducible nitric-oxide synthase (iNOS), and cyclooxygenase (COX)-II. It also inhibited the activation of murine iNOS and COX-II promoter activity. However, of the two common responsive elements of iNOS and COX-II promoters, nuclear factor-kappaB (NF-kappaB) and adaptor protein (AP)1, only AP1 activation was inhibited by tylophorine in the LPS/IFNgamma-stimulated RAW264.7 cells. Further studies showed that the tylophorine enhanced the phosphorylation of Akt and thus decreased the expression and phosphorylation levels of c-Jun protein, thereby causing the subsequent inhibition of AP1 activity. Furthermore, the tylophorine was able to block mitogen-activated protein/extracellular signal-regulated kinase kinase 1 activity and its downstream signaling activation of NF-kappaB and AP1. Thus, NSTP0G01 exerts its anti-inflammatory effects by inhibiting expression of the proinflammatory factors and related signaling pathways.
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PMID:Anti-inflammatory mechanisms of phenanthroindolizidine alkaloids. 1633 92


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