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

The expression of inducible nitric oxide synthase (iNOS) by macrophages is stimulated by coexposure to IFN-gamma and a number of stimuli, including TNF-alpha. Recent work has shown that TNF-alpha activates members of the mitogen-activated protein kinase family that subsequently trans-activate transcription factors implicated in the regulation of iNOS expression. The objective of this study was to systematically evaluate the role of: 1) p42mapk/erk2, 2) p46 c-Jun NH2-terminal kinase/stress-activated protein kinase (p46 JNK/SAPK), and 3) p38mapk in the induction of iNOS expression during costimulation of mouse macrophages with IFN-gamma and TNF-alpha. All three kinases were activated during costimulation with IFN-gamma and TNF-alpha. However, specific antagonism of the p42mapk/erk2 and p38mapk with PD98059 and SKF86002, respectively, had no effect on the induction of iNOS expression. In contrast, blockade of all three kinases with N-acetylcysteine completely blocked the induction of iNOS expression. In addition, specific antagonism of the JNK/SAPK upstream kinases MEKK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase) and MKK4 (mitogen-activated protein kinase kinase 4) with dominant inhibitory mutants blocked transcriptional activation of the iNOS promoter in response to costimulation with IFN-gamma and TNF-alpha. Collectively, these findings support the involvement of p46 JNK/SAPK and its upstream kinases in regulating the induction of iNOS following ligation of the TNF-alpha receptor CD120a (p55) in the presence of IFN-gamma.
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PMID:Evaluation of the role of mitogen-activated protein kinases in the expression of inducible nitric oxide synthase by IFN-gamma and TNF-alpha in mouse macrophages. 988 15

Nitric oxide production by macrophages is principally regulated by the calcium-independent enzyme, inducible nitric oxide synthase (iNOS). Both lipopolysaccharide and TNF-alpha synergize with IFN-gamma in the expression of iNOS with subsequent production of nitric oxide. Previous work has shown that IL-4 downregulates iNOS and nitric oxide expression by macrophages stimulated with LPS and IFN-gamma. In this study, we found that IL-4 also downregulated iNOS and nitric oxide expression induced by IFN-gamma and TNF-alpha and in mouse macrophages. Because various members of the mitogen-activated protein kinases and their upstream kinases have been shown to directly or indirectly activate a number of transcription factors including AP-1 and NFkappaB, we examined the effects of IL-4 on TNF-alpha activation of the MAPKs. Our results show that IL-4 modestly inhibited JNK/SAPK and ERK activation by TNF-alpha. Previously, we showed that selective pharmacologic inhibition of the ERK and/or p38mapk pathway did not affect NO2- expression. Treatment of cells with the chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) showed a dose-response inhibition of NO2- expression. NPPB was also found to inhibit ERK and JNK/SAPK activation but not p38mapk with TNF-alpha stimulation. The discordance between the marked degree of inhibition of iNOS transcript by IL-4 and the modest inhibition of JNK/SAPK and ERK suggests that the mechanism by which IL-4 inhibits iNOS transcription appears more complex than a mere inhibition of these MAPKs.
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PMID:Potential role of the JNK/SAPK signal transduction pathway in the induction of iNOS by TNF-alpha. 991 6

The induction of inducible nitric oxide synthase (iNOS) by proinflammatory cytokines was studied in an oligodendrocyte progenitor cell line in relation to mitogen-activated protein kinase (MAPK) activation and cytokine-mediated cytotoxicity. When introduced individually to cultures of CG4 cells, the cytokines, i.e., tumor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1), and interferon-gamma (IFN gamma), had either minimal (TNF alpha) or no (IL-1 and IFN gamma) detectable stimulatory effect on the production of nitric oxide. However, combinations of these factors, in particular, TNF alpha plus IFN gamma, elicited a strong enhancement of nitric oxide synthesis and, as revealed by western blot and RT-PCR analysis, the expression of iNOS. TNF alpha and IL-1 were able to activate p38 MAPK in a time- and dose-dependent manner and together showed a combinatorial effect. In contrast, IFN gamma neither activated on its own nor enhanced the activation of p38 MAPK in response to TNF alpha and IL-1. However, a specific inhibitor of p38 MAPK, i.e., SB203580, inhibited the induction of iNOS in cytokine combination-treated cells in a dose-dependent manner, thereby suggesting a role for the MAPK cascade in regulating the induction of iNOS gene expression in cytokine-treated cells. Blocking of nitric oxide production by an inhibitor of iNOS, i.e., nitro-L-arginine methyl ester, had a minimal protective effect against cytokine-mediated cytotoxicity that occurred before the elevation of nitric oxide levels, thereby indicating temporal and functional dissociation of nitric oxide production from cell killing.
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PMID:Cytokine induction of inducible nitric oxide synthase in an oligodendrocyte cell line: role of p38 mitogen-activated protein kinase activation. 993 Jul 18

The genes encoding inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2, also known as prostaglandin-endoperoxide synthase-2) are induced in many types of cells in response to proinflammatory cytokines. We have previously shown that interleukin-1beta (IL) stimulates iNOS and COX-2 mRNA in cardiac myocytes. Because IL has been shown to activate mitogen-activated protein kinase (MAPK) signaling pathways in many different cells, we tested whether the p42/44 and p38 MAPK pathways were involved in IL stimulation of iNOS and COX-2, using a specific inhibitor of p42/44 activation, PD98059 (PD), and the p38 inhibitor SB205380 (SB). Nitrites were measured using the Griess reagent, prostaglandin PGE2 by an enzyme immunoassay, iNOS and COX-2 protein by Western blot analysis, and iNOS mRNA by Northern blot analysis. Tested separately, the p38 kinase and MAPK inhibitors partially reduced IL stimulation of nitrite, iNOS protein, and iNOS mRNA; used together, they completely abolished the effect of IL. SB and PD inhibited IL-stimulated COX-2 protein by 60% and 80%, respectively, and IL-stimulated COX-2 protein was totally prevented by the combination of inhibitors. PGE2 production was inhibited more than 99% by either drug alone, suggesting a posttranslational effect on enzyme activity. To test whether this posttranslational effect involved the cytosolic phospholipase A2 (cPLA2) isoform, Western blots were probed for cPLA2 protein. Results indicated that IL stimulated cPLA2 activity and synthesis, which was inhibited by SB but not PD. These data indicate that (1) IL induction of iNOS synthesis depends on both the p42/44 and p38 signaling pathways, acting primarily at the level of transcriptional regulation; and (2) IL regulation of COX-2 synthesis involves the p42/44 and p38 signaling pathways, with an additional level of regulation occurring posttranslationally, perhaps at the level of activation of the cPLA2 isoform, which may be involved in intracellular signaling, as well as regulation of arachidonic acid release for COX-2 activity.
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PMID:Interleukin-1beta regulation of inducible nitric oxide synthase and cyclooxygenase-2 involves the p42/44 and p38 MAPK signaling pathways in cardiac myocytes. 993 Nov 17

Whether p38 and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase cascades are required for inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF) accumulation in RAW 264.7 murine macrophages exposed to lipopolysaccharide (LPS) plus recombinant interferon-gamma (rIFN-gamma) was investigated. By use of Western blotting for iNOS detection and ELISA for quantitation of TNF secretion, three selective inhibitors of these pathways were tested (the p38 inhibitors SB202190 and SB203580 and the MEK 1,2/ERK inhibitor PD98059). Dose-related inhibition of iNOS production was demonstrated when inhibitors were added 1 h before, simultaneously with, or 1 h after LPS plus rIFN-gamma stimulation. In contrast, inhibition of TNF secretion was observed only when cells were preincubated with these agents. Thus, both the p38 and ERK pathways are involved in the up-regulation of iNOS and TNF production by murine macrophages, and specific inhibitors of these pathways block macrophage iNOS production even when added 1 h after activation of these cells.
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PMID:Specific inhibitors of p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways block inducible nitric oxide synthase and tumor necrosis factor accumulation in murine macrophages stimulated with lipopolysaccharide and interferon-gamma. 1006 90

Intracellular protozoan parasites of the genus Leishmania antagonize host defense mechanisms by interfering with cell signaling in macrophages. In this report, the impact of Leishmania donovani on mitogen-activated protein (MAP) kinases and nitric oxide synthase (NOS) expression in the macrophage cell line RAW 264 was investigated. Overnight infection of cells with leishmania led to a significant decrease in phorbol-12-myristate-13-acetate (PMA)-stimulated MAP kinase activity and inhibited PMA-induced phosphorylation of the MAP kinase substrate and transcription factor Elk-1. Simultaneously, leishmania infection markedly attenuated the induction of c-FOS and inducible nitric oxide synthase (iNOS) expression in response to PMA and gamma interferon (IFN-gamma), respectively. These effects correlated with decreased phosphorylation of p44 and p42 MAP kinases on tyrosine residues. Consistent with the latter finding, lysates prepared from leishmania-infected cells contained an activity that dephosphorylated MAP kinase in vitro, suggesting the possibility of a phosphatase acting in vivo. Attenuation of both MAP kinase activity and c-FOS and iNOS expression was reversed by treatment of macrophages with sodium orthovanadate prior to infection. It was also found that the specific activity of the Src homology 2 domain containing tyrosine phosphatase (SHP-1) toward MAP kinase was markedly increased in leishmania-infected cells. These findings indicate that infection with L. donovani attenuates MAP kinase signaling and c-FOS and iNOS expression in macrophages by activating cellular phosphotyrosine phosphatases. This may represent a novel mechanism of macrophage deactivation during intracellular infection.
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PMID:Activation of phosphotyrosine phosphatase activity attenuates mitogen-activated protein kinase signaling and inhibits c-FOS and nitric oxide synthase expression in macrophages infected with Leishmania donovani. 1041 74

Macrophages comprise the major population of cells infiltrating pancreatic islets during the early stages of infection in DBA/2 mice by the D variant of encephalomyocarditis virus (EMC-D virus). Inactivation of macrophages prior to viral infection almost completely prevents EMC-D virus-induced diabetes. This investigation was initiated to determine whether a tyrosine kinase signalling pathway might be involved in the activation of macrophages by EMC-D virus infection and whether tyrosine kinase inhibitors might, therefore, abrogate EMC-D virus-induced diabetes in vivo. When isolated macrophages were infected with EMC-D virus, inducible nitric oxide synthase mRNA was expressed and nitric oxide was subsequently produced. Treatment of macrophages with the tyrosine kinase inhibitor tyrphostin AG126, but not tyrphostin AG556, prior to EMC-D virus infection blocked the production of nitric oxide. The infection of macrophages with EMC-D virus also resulted in the activation of the mitogen-activated protein kinases (MAPKs) p42(MAPK/ERK2)/p44(MAPK/ERK1), p38(MAPK), and p46/p54(JNK). In accord with the greater potency of AG126 than of AG556 in blocking EMC-D virus-mediated macrophage activation, the incidence of diabetes in EMC-D virus-infected mice treated with AG126 (25%) was much lower than that in AG556-treated (75%) or vehicle-treated (88%) control mice. We conclude that EMC-D virus-induced activation of macrophages resulting in macrophage-mediated beta-cell destruction can be prevented by the inhibition of a tyrosine kinase signalling pathway involved in macrophage activation.
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PMID:Prevention of encephalomyocarditis virus-induced diabetes in mice by inhibition of the tyrosine kinase signalling pathway and subsequent suppression of nitric oxide production in macrophages. 1048 7

The expression of inducible nitric oxide synthase (iNOS) is a characteristic response to inflammation and can be inhibited with sodium salicylate. We used the cytokine-induced iNOS induction in cardiac fibroblasts as a model system in which to test the hypothesis that effects on mitogen-activated protein kinases (MAPKs) may explain the mechanism by which salicylate exerts its anti-inflammatory effects. Tumor necrosis factor-alpha (TNF-alpha) alone can induce extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase activity in a rapid and transient manner, whereas interferon-gamma (IFN-gamma) can induce only ERK. The inhibition of either the ERK pathway or p38 MAPK activity with selective inhibitors blocked cytokine-induced iNOS protein and nitrite production. Salicylate treatment inhibited iNOS expression induced by TNF-alpha and IFN-gamma and attenuated the phosphorylation of ERK by TNF-alpha and IFN-gamma either alone or in combination. Salicylate had no obvious effect on the activation of p38 MAPK or c-Jun N-terminal kinase. The results showed that salicylate inhibited the phosphorylation of ERK and iNOS expression induced by cytokines in a dose-dependent manner and suggested that salicylate exerts its anti-inflammatory action in part through inhibition of the ERK pathway and iNOS induction.
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PMID:Salicylate inhibition of extracellular signal-regulated kinases and inducible nitric oxide synthase. 1060 Nov 28

Eosinophilic meningitis or meningoencephalitis caused by Angiostrongylus cantonensis is endemic to the Pacific area of Asia, especially Taiwan, Thailand, and Japan. Although eosinophilia is an important clinical manifestation of A. cantonensis infection, the role of eosinophils in the progress of the infection remains to be elucidated. In this experiment, we showed that A. cantonensis-caused eosinoplia and inflammation might lead to the induction of NF-kappaB and protooncogene expression via activation of the tyrosine phosphorylation signal pathway. After mice were infected daily with 30 third-stage larvae of A. cantonensis by oral adminstration for 6 weeks, no significant differences PKC-alpha, MEK-1, ERK-2, JNK, and p38 protein expression were found between the control and infected mice. However, the protein tyrosine phosphorylation levels, NF-kappaB, and iNOS protein products were significantly increased by 3.5-, 3.3-, and 6.3-fold, respectively, after 3 weeks of A. cantonensis infection. The same pattern was found for c-Myc, c-Jun, and c-Fos proteins, which were elevated by 3.2-, 2.3-, and 3.4-fold, respectively, compared to control animals after 3 weeks. The expression potency of these proteins started increasing in week 1, reaching maximal induction in week 3, and then declining in week 5 after A. cantonensis infection. Another consistent result was noted in the pathological observations, including eosinophilia, leukocyte infiltration, granulomatous reactions, and time responses in brain tissues of infected mice. These data suggest that the development of brain injury by eosinophlia of A. cantonensis infection is associated with NF-kappaB and/or nuclear protooncogenes expression, which is activated by the tyrosine phosphorylation pathway.
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PMID:Development of brain injury in mice by Angiostrongylus cantonensis infection is associated with the induction of transcription factor NF-kappaB, nuclear protooncogenes, and protein tyrosine phosphorylation. 1096 48

In the present study the effects of 17beta-estradiol on microglial activation are described. Estrogen replacement therapy has been associated with decreased severity of age-related neurodegenerative diseases such as Alzheimer's disease, and estrogens have potent immunosuppressive properties outside of the brain. To determine the role that microglial cells might play in estrogen-mediated neuroprotection, primary rat microglia and N9 microglial cell lines were treated with increasing doses of 17beta-estradiol before or during immunostimulation by lipopolysaccharide, phorbol ester, or interferon-gamma. Pretreatment with 17beta-estradiol, but not 17alpha-estradiol or progesterone, dose dependently attenuated microglial superoxide release and phagocytic activity. Additionally, 17beta-estradiol attenuated increases in inducible nitric oxide synthase protein expression, but did not alter nuclear factor-KB activation. The antiinflammatory effects of 17beta-estradiol were blocked by the antiestrogen ICI 182,780. Additionally, 17beta-estradiol induced rapid phosphorylation of the p42/p44 mitogen-activated protein kinase (MAP kinase), and the MAP kinase inhibitor PD 98059 blocked the antiinflammatory effects of 17beta-estradiol. Overall, these results suggest that estrogen receptor-dependent activation of MAP kinase is involved in estrogen-mediated antiinflammatory pathways in microglial cells. These results describe a novel mechanism by which estrogen may attenuate the progression of neurodegenerative disease and suggest new pathways for therapeutic intervention in clinical settings.
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PMID:Antiinflammatory effects of estrogen on microglial activation. 1101 19


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