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)

Under normal and pathological conditions, brain cells release nucleotides that regulate a wide range of cellular responses due to activation of P2 nucleotide receptors. In this study, the effect of extracellular nucleotides on IFN gamma-induced NO release in murine BV-2 microglial cells was investigated. BV-2 cells expressed mRNA for metabotropic P2Y and ionotropic P2X receptors. Among the P2 receptor agonists tested, ATP, ADP, 2',3'-O-(4-benzoylbenzoyl)-ATP (BzATP), and 2-methylthio-ATP (2-MeSATP), but not UTP, enhanced IFN gamma-induced iNOS expression and NO production, suggesting that the uridine nucleotide receptors P2Y2 and P2Y6 are not involved in this response. U0126, an antagonist for MEK1/2, a kinase that phosphorylates the extracellular signal-regulated kinases ERK1/2, decreased IFN gamma-induced NO production. BzATP, a potent P2X7 receptor agonist, was more effective than ATP, ADP, or 2-MeSATP at enhancing IFN gamma-induced ERK1/2 phosphorylation. Consistent with activation of the P2X7 receptor, periodate-oxidized ATP, a P2X7 receptor antagonist, and suramin, a non-specific P2 receptor antagonist, inhibited the effect of ATP or BzATP on IFN gamma-induced NO production, whereas pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), an antagonist of several P2X receptor subtypes, was ineffective. These results suggest that activation of P2X7 receptors may contribute to inflammatory responses in microglial cells seen in neurodegenerative diseases.
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PMID:P2X7 nucleotide receptor activation enhances IFN gamma-induced type II nitric oxide synthase activity in BV-2 microglial cells. 1451 Nov 12

1. Although capsaicin analogs might be a potential strategy to manipulate inflammation, the mechanism is still unclear. In this study, the effects and action mechanisms of vanilloid analogs on iNOS and COX-2 expression were investigated in RAW264.7 macrophages. 2. Capsaicin and resiniferatoxin (RTX) can inhibit LPS- and IFN-gamma-mediated NO production, and iNOS protein and mRNA expression with similar IC50 values of around 10 microm. 3. Capsaicin also transcriptionally inhibited LPS- and PMA-induced COX-2 expression and PGE2 production. However, this effect exhibited a higher potency (IC50: 0.2 microm), and RTX failed to elicit such responses at 10 microm. 4. Interestingly, we found that capsazepine, a competitive TRPV1 antagonist, did not prevent the inhibition elicited by capsaicin or RTX. Nevertheless, it mimicked vanilloids in inhibiting iNOS/NO and COX-2/PGE2 induction with an IC50 value of 3 microm. RT-PCR and immunoblotting analysis excluded the expression of TRPV1 in RAW264.7 macrophages. 5. The DNA binding assay demonstrated the abilities of vanilloids to inhibit LPS-elicited NF-kappaB and AP-1 activation and IFN-gamma-elicited STAT1 activation. The reporter assay of AP-1 activity also supported this action. 6. The kinase assay indicated that ERK, JNK, and IKK activation by LPS were inhibited by vanilloids. 7. In conclusion, vanilloids can modulate the expression of inflammatory iNOS and COX-2 genes in macrophages through interference with upstream signalling events of LPS and IFN-gamma. These findings provide new insights into the potential benefits of the active ingredient in hot chilli peppers in inflammatory conditions.
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PMID:Signal transduction for inhibition of inducible nitric oxide synthase and cyclooxygenase-2 induction by capsaicin and related analogs in macrophages. 1453 Feb 14

Sesame antioxidants have been shown to inhibit lipid peroxidation and regulate cytokine production. In this study, we focused on the effect of sesamin and sesamolin, on nitric oxide (NO) induction by lipopolysaccharides (LPS) in the murine microglial cell line BV-2 and rat primary microglia. The results showed that sesamin and sesamolin significantly inhibited NO production, iNOS mRNA and protein expression in LPS-stimulated BV-2 cells. Sesamin or sesamolin significantly reduced LPS-activated p38 MAPK of BV-2 cells. Furthermore, SB203580, a specific inhibitor of p38 MAP kinase, dose-dependently inhibited NO production in LPS-stimulated BV-2 cells. Taken together, the inhibition of NO production might be due to the reduction of LPS-induced p38 MAPK signal pathway by sesamin and sesamolin.
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PMID:Effect of sesame antioxidants on LPS-induced NO production by BV2 microglial cells. 1453 26

The stress-activated protein kinase c-Jun NH2-terminal kinase (JNK) is a central signal for interleukin-1beta (IL-1beta)-induced apoptosis in insulin-producing beta-cells. The cell-permeable peptide inhibitor of JNK (JNKI1), that introduces the JNK binding domain (JBD) of the scaffold protein islet-brain 1 (IB1) inside cells, effectively prevents beta-cell death caused by this cytokine. To define the molecular targets of JNK involved in cytokine-induced beta-cell apoptosis we investigated whether JNKI1 or stable expression of JBD affected the expression of selected pro- and anti-apoptotic genes induced in rat (RIN-5AH-T2B) and mouse (betaTC3) insulinoma cells exposed to IL-1beta. Inhibition of JNK significantly reduced phosphorylation of the specific JNK substrate c-Jun (p<0.05), IL-1beta-induced apoptosis (p<0.001), and IL-1beta-mediated c-fos gene expression. However, neither JNKI1 nor JBD did influence IL-1beta-induced NO synthesis or iNOS expression or the transcription of the genes encoding mitochondrial manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase rho (GSTrho), heat shock protein (HSP) 70, IL-1beta-converting enzyme (ICE), caspase-3, apoptosis-inducing factor (AIF), Bcl-2 or Bcl-xL. We suggest that the anti-apoptotic effect of JNK inhibition by JBD is independent of the transcription of major pro- and anti-apoptotic genes, but may be exerted at the translational or posttranslational level.
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PMID:The JNK binding domain of islet-brain 1 inhibits IL-1 induced JNK activity and apoptosis but not the transcription of key proapoptotic or protective genes in insulin-secreting cell lines. 1456 87

Peroxisome proliferator-activated receptor (PPAR)gamma agonists, such as 15-deoxy-delta 12,14-prostaglandin J2 (PGJ2) and troglitazone, have been shown to elicit anti-inflammatory effects in pancreatic beta-cells that include inhibition of cytokine-stimulated inducible nitric oxide synthase (iNOS) gene expression and production of nitric oxide. In addition, these ligands impair IL-1-induced NF-kappaB and MAPK as well as IFN-gamma-stimulated signal transducer and activator of transcription (STAT)1 activation in beta-cells. The purpose of this study was to determine if PPARgamma activation participates in the anti-inflammatory actions of PGJ2 in beta-cells. Pretreatment of RINm5F cells for 6 h with PGJ2 results in inhibition of IL-1-stimulated IkappaB degradation and IFN-gamma-stimulated STAT1 phosphorylation. Overexpression of a dominant-negative (dn) PPARgamma mutant or treatment with the PPARgamma antagonist GW-9662 does not modulate the inhibitory actions of PGJ2 on cytokine signaling in RINm5F cells. Although these agents fail to attenuate the inhibitory actions of PGJ2 on cytokine signaling, they do inhibit PGJ2-stimulated PPARgamma response element reporter activity. Consistent with the inability to attenuate the inhibitory actions of PGJ2 on cytokine signaling, neither dnPPARgamma nor GW-9662 prevents the inhibitory actions of PGJ2 on IL-1-stimulated iNOS gene expression or nitric oxide production by RINm5F cells. These findings support a PPARgamma-independent mechanism by which PPARgamma ligands impair cytokine signaling and iNOS expression by islets.
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PMID:PPARgamma is not required for the inhibitory actions of PGJ2 on cytokine signaling in pancreatic beta-cells. 1460 76

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

Nitric oxide (NO) and reactive oxygen species exert multiple modulating effects on inflammation and play a key role in the regulation of immune responses. They affect virtually every step of the development of inflammation. Low concentrations of nitric oxide produced by constitutive and neuronal nitric oxide synthases inhibit adhesion molecule expression, cytokine and chemokine synthesis and leukocyte adhesion and transmigration. Large amounts of NO, generated primarily by iNOS can be toxic and pro-inflammatory. Actions of nitric oxide are however not dependent primarily on the enzymatic source, but rather on the cellular context, NO concentration (dependent on the distance from NO source) and initial priming of immune cells. These observations may explain difficulties in determining the exact role of NO in Th1 and Th2 lymphocyte balance in normal immune responses and in allergic disease. Similarly superoxide anion produced by NAD(P)H oxidases present in all cell types participating in inflammation (leukocytes, endothelial and other vascular cells etc) may lead to toxic effects, when produced at high levels during oxidative burst, but may also modulate inflammation in a far more discrete way, when continuously produced at low levels by NOXs (non-phagocytic oxidases). The effects of both nitric oxide and superoxide in immune regulation are exerted through multiple mechanisms, which include interaction with cell signalling systems like cGMP, cAMP, G-protein, JAK/STAT or MAPK dependent signal transduction pathways. They may also lead to modification of transcription factors activity and in this way modulate the expression of multiple other mediators of inflammation. Moreover genetic polymorphisms exist within genes encoding enzymes producing both NO and superoxide. The potential role of these polymorphisms in inflammation and susceptibility to infection is discussed. Along with studies showing increasing role of NO and free radicals in mediating inflammatory responses drugs which interfere with these systems are being introduced in the treatment of inflammation. These include statins, angiotensin receptor blockers, NAD(P)H oxidase inhibitors, NO-aspirin and others. In conclusion in this mini-review we discuss the mechanisms of nitric oxide and superoxide dependent modulation of inflammatory reactions in experimental animals and humans. We also discuss potential roles of nitric oxide as a mediator of allergic inflammation.
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PMID:Nitric oxide and superoxide in inflammation and immune regulation. 1472 4

Prostaglandins are lipid mediators, generated by cyclooxygenase (COX), that have been shown to participate in the regulation of virus replication and the modulation of inflammatory responses following infection. A number of studies support a role for PGE2 in the modulation of virus replication and virulence in a cell type and virus selective manner. Virus infection also stimulates the expression of a number of proinflammatory gene products, including COX-2, inducible nitric oxide synthase (iNOS) as well as proinflammatory cytokines. This review will focus on the mechanisms by which proinflammatory prostaglandin production regulates virus replication and virulence. In addition, the signaling pathways that are activated during a virus infection, and that regulate proinflammatory gene expression in macrophages will be reviewed. Specific attention will be placed on the ability of virus infection to activate multiple signaling cascades (such as PKR, MAPK, iPLA2, NF-kappaB) and how these pathways are integrated in the regulation of individual target gene expression.
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PMID:The role and regulation of COX-2 during viral infection. 1473 33

In this study, we examined the signal transduction of dibutyryl cyclic adenosine monophosphate (dBcAMP) to stimulate the release of nitric oxide (NO) and interleukin-6 (IL-6) from J774 macrophages. These actions of dBcAMP were diminished by the presence of the inhibitors of protein kinase A (PKA), protein kinase C (PKC), p38 MAPK and nuclear factor-kappa B (NF-kappaB). In contrast, Go 6976 and PD98059 had no significant effects. Consistently, dBcAMP caused membrane translocation of PKCbetaII, delta, mu, lambda and zeta isoforms, and increased atypical protein kinase C (aPKC) and p38 MAPK activities. The nuclear translocation and DNA-binding study revealed that dBcAMP stimulated NF-kappaB, activator protein-1 (AP-1), and CAAT/enhancer-binding protein (c/EBPbeta). Via PKA, PKC and p38 MAPK-dependent signals, dBcAMP also induced inhibitory subunit of NF-kappaB (IkappaB) degradation, IkappaB kinase (IKK) activation, nuclear translocation of NF-kappaB subunit p65 and its association with the CREB-binding protein (CBP). These results illustrate that PKA activation in macrophages is able to stimulate PKC and p38 MAPK, which lead to IKK-dependent NF-kappaB activation and contribute to the induction of inducible nitric oxide synthase (iNOS) and IL-6 genes.
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PMID:PKA-dependent activation of PKC, p38 MAPK and IKK in macrophage: implication in the induction of inducible nitric oxide synthase and interleukin-6 by dibutyryl cAMP. 1475 42

Bacterial lipopolysaccharide (LPS) is known to induce endotoxic shock with inducible nitric oxide (NO) synthase (iNOS) expression and NO production. However, the major place for NO production in shock remains unclear. Although there is some literature about p38 mitogen-activated protein kinase (MAPK) in regulating LPS-induced iNOS expression, the results are contradictory. To interpret the precise cell mechanism and the role of p38 MAPK in the expression of iNOS during endotoxic shock, we carried out the following investigations. A severe endotoxic shock model was reproduced in mice 6 h after LPS injection. The plasma NO level was increased in a dose- and time-dependent manner after LPS stimulation and was suppressed by administration of SB203580 [4-(4-fluorophenyl)-2-4-methylsulfonylphenyl-5-(4-pyridyl) imidazole], a highly specific inhibitor of p38 MAPK. The iNOS expression was increased in many organs, including heart, liver, spleen, lung, gut, and kidney in endotoxic shock. Among them, the highest expression of iNOS mRNA and protein was in the lung, moderate expression was in the spleen and kidney, and the lowest expression was in the heart, gut, and liver. The level of expression in lung was 5.5 times that of iNOS mRNA and was 3.1 times that of iNOS protein than in heart, and 1.6 and 1.8 times that of iNOS mRNA and 1.7 and 1.4 times that of iNOS protein than in spleen and kidney, respectively. The p38 MAPK activity increased after LPS injection, and SB203580 markedly reduced LPS-induced expressions of iNOS protein and mRNA in the lung. The results indicates that lung, spleen, and kidney are the major places for iNOS expression in endotoxic shock and are important therapeutic target organs for attenuating NO production in shock treatment.
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PMID:Lung, spleen, and kidney are the major places for inducible nitric oxide synthase expression in endotoxic shock: role of p38 mitogen-activated protein kinase in signal transduction of inducible nitric oxide synthase expression. 1477 43


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