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)

Airway smooth muscle (ASM) is a potential source of multiple proinflammatory cytokines during airway inflammation. In the present study, we examined a requirement for mitogen-activated protein (MAP) kinase activation for interleukin (IL)-1beta-stimulated GM-CSF, RANTES, and eotaxin release. IL-1beta induced concentration-dependent phosphorylation of p42/p44 extracellular signal-regulated kinases (ERKs), p38 MAP kinase, and c-Jun amino-terminal kinase (SAPK/JNK). p42/p44 ERK and p38 MAP kinase phosphorylation peaked at 15 min and remained elevated up to 4 h. SAPK/JNK phosphorylation also peaked at 15 min but fell to baseline within 60 min. SB 203580 selectively inhibited IL-1beta-stimulated activation of p38 MAP kinase; U 0126 was selective against p42/p44 ERK activity. SB 202474, an inactive analog, had no effect on p42/p44 ERK, p38 MAP kinase, or SAPK/JNK activation, or on eotaxin or RANTES release. Eotaxin release was inhibited by SB 203580 and U 0126, whereas RANTES release was prevented by U 0126 only. GM-CSF release was inhibited by U 0126 but enhanced by SB 203580. These data indicate that RANTES release is dependent on p42/p44 ERK activation but occurs independently of p38 MAP kinase activity. Eotaxin release, however, is dependent on both p38 MAP kinase- and p42/p44 ERK-dependent mechanisms. GM-CSF release is p42/p44 ERK dependent and is tonically suppressed by a mechanism that is partially dependent on p38 MAP kinase, though direct inhibition of cyclooxygenase (COX) activity due to poor inhibitor selectivity may also contribute.
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PMID:Inhibitors of mitogen-activated protein kinases differentially regulate eosinophil-activating cytokine release from human airway smooth muscle. 1152 Jul 38

In rat membranous nephropathy, complement C5b-9 induces glomerular epithelial cell (GEC) injury and proteinuria, which is partially mediated by eicosanoids. Rat GEC in culture express cyclooxygenase (COX)-1 constitutively, whereas COX-2 expression is induced by C5b-9. Both isoforms contribute to complement-induced prostaglandin generation. The present study addresses mechanisms of complement-induced COX-2 expression in GEC. Downregulation of protein kinase C (PKC) blunted complement-induced upregulation of COX-2 mRNA. Complement and phorbol 12-myristate 13-acetate (PMA) both stimulated COX-2 promoter activity. C5b-9 activated c-Jun NH(2)-terminal kinase (JNK), and inhibition of JNK activity by transfection of a kinase-inactive JNK1 partially inhibited complement-induced (but not PMA-induced) COX-2 promoter activation. Conversely, a constitutively active mitogen-activated protein or extracellular signal-regulated kinase kinase kinase (MEKK)-1, a kinase upstream of JNK, increased COX-2 promoter activity. MEKK-induced COX-2 promoter activation was not affected by downregulation of PKC and was augmented by PMA. Thus, in GEC, PKC and JNK pathways contribute independently to complement-induced COX-2 expression. Nuclear factor-kappaB was also activated by complement in GEC but did not contribute to complement-induced COX-2 upregulation.
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PMID:Complement C5b-9 induces cyclooxygenase-2 gene transcription in glomerular epithelial cells. 1159 42

Several studies have demonstrated unequivocally that certain nonsteroidal anti-inflammatory drugs (NSAIDs) such as sodium salicylate, sulindac, ibuprofen, and flurbiprofen cause anti-inflammatory and antiproliferative effects independent of cyclooxygenase activity and prostaglandin synthesis inhibition. These effects are mediated through inhibition of certain transcription factors such as NF-kappaB and AP-1. The respective NSAIDs might interfere directly with the transcription factors, but their effects are probably mediated predominantly through alterations of the activity of cellular kinases such as IKKbeta, Erk, p38 MAPK, or Cdks. These effects apparently are not shared by all NSAIDs, since indomethacin failed to inhibit NF-kappaB and AP-1 activation as well as Erk and Cdk activity. In contrast, indomethacin was able to activate PPARgamma, which was not affected by sodium salicylate or aspirin. The differences in cyclooxygenase-independent mechanisms may have consequences for the specific use of these drugs in individual patients because additional effects may either enhance the efficacy or reduce the toxicity of the respective compounds.
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PMID:Cyclooxygenase-independent actions of cyclooxygenase inhibitors. 1164 Dec 33

Phosphodiesterase 4D5 is the sole PDE4D cAMP phosphodiesterase isoform expressed in human aortic smooth muscle cells (HASMC). Phorbol 12-myristate 13-acetate (PMA) challenge of HASMC rapidly activated PDE4D5 through a process ablated by the mitogen-activated protein kinase kinase inhibitor PD98059. PMA elicited an inhibitory effect on PDE4D5 activity in HASMC treated with the cyclooxygenase (COX) inhibitor indomethacin, the COX-2 selective inhibitor NS-398, the phospholipase A(2) inhibitor quinacrine, and the cAMP-dependent protein kinase A (PKA) inhibitor H89. PMA challenge of COS-1 cells elicited the rapid inhibition and phosphorylation of both recombinant and endogenous PDE4D5 in a manner ablated by PD98059 and not seen in S651A mutant PDE4D5. PMA promoted the generation of PGE(2) in the medium of HASMC and caused activation of both extracellular signal-regulated kinase (ERK) and PKA through a process ablated by indomethacin, NS-398, quinacrine, and PD98059. Exogenous prostaglandin (PG) E(2) increased cAMP levels and activated PKA in HASMC. COX-2 was expressed in HASMC but not in COS-1 cells. Forskolin challenge of COS-1 cells activated PDE4D5 by causing the PKA-mediated phosphorylation of Ser126 as detected using a novel phosphospecific antiserum. PMA challenge of HASMC elicited phosphorylation of the stimulatory PKA-specific phosphorylation site, Ser126 in PDE4D5 in a manner ablated by PD98059, indomethacin, and H89. We propose that, in HASMC, PMA activates PDE4D5 through an ERK-controlled autocrine mechanism. This involves PGE(2) generation, which causes activation of adenylyl cyclase, allowing PKA to elicit net activation of PDE4D5 by phosphorylation at Ser126.
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PMID:Phorbol 12-myristate 13-acetate triggers the protein kinase A-mediated phosphorylation and activation of the PDE4D5 cAMP phosphodiesterase in human aortic smooth muscle cells through a route involving extracellular signal regulated kinase (ERK). 1164 39

Helicobacter pylori infection elicits persistent neutrophil infiltration in gastric mucosa. The expression of cyclooxygenase (COX) -2 by the neutrophils results in prostaglandin (PG) E2 synthesis, which may account for alterations in tissue homeostasis. In this study, we found that COX-2 mRNA was up-regulated in the neutrophils when stimulated with both H. pylori water extract (HPWE) and live H. pylori in a transwell model and determined by quantitative RT-PCR. PGE2 synthesis was also enhanced in the neutrophils activated by both the HPWE and live H. pylori. A specific COX-2 inhibitor (NS-398) blocked PGE2 synthesis, and an anti-ulcer agent (rebamipide) suppressed it dose dependently. An NF-kappaB inhibitor (pyrrolidine dithiocarbamate), a MAP kinase (MEK) inhibitor (PD98059), and a p38 MAP kinase inhibitor (SB203580) significantly suppressed the COX-2 gene transcription and PGE2 synthesis in the neutrophils. In conclusion, H. pylori water-soluble proteins may enhance the COX-2 expression, and this action could be mediated through the NF-kappaB and MAP kinase signaling pathways. The increased section of PGE2 by the neutrophils may play a proinflammatory role in the gastric mucosal response to H. pylori.
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PMID:Expression of cyclooxygenase-2 in human neutrophils activated by Helicobacter pylori water-soluble proteins: possible involvement of NF-kappaB and MAP kinase signaling pathway. 1168 Jun 8

The fruit hull of mangosteen, Garcinia mangostana L., has been used for many years as a medicine for treatment of skin infection, wounds, and diarrhea in Southeast Asia. In the present study, we examined the effect of gamma-mangostin, a tetraoxygenated diprenylated xanthone contained in mangosteen, on arachidonic acid (AA) cascade in C6 rat glioma cells. gamma-Mangostin had a potent inhibitory activity of prostaglandin E2 (PGE2) release induced by A23187, a Ca2+ ionophore. The inhibition was concentration-dependent, with the IC50 value of about 5 microM. gamma-Mangostin had no inhibitory effect on A23187-induced phosphorylation of p42/p44 extracellular signal regulated kinase/mitogen-activated protein kinase or on the liberation of [14C]-AA from the cells labeled with [14C]-AA. However, gamma-mangostin concentration-dependently inhibited the conversion of AA to PGE2 in microsomal preparations, showing its possible inhibition of cyclooxygenase (COX). In enzyme assay in vitro, gamma-mangostin inhibited the activities of both constitutive COX (COX-1) and inducible COX (COX-2) in a concentration-dependent manner, with the IC50 values of about 0.8 and 2 microM, respectively. Lineweaver-Burk plot analysis indicated that gamma-mangostin competitively inhibited the activities of both COX-1 and -2. This study is a first demonstration that gamma-mangostin, a xanthone derivative, directly inhibits COX activity.
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PMID:Inhibition of cyclooxygenase and prostaglandin E2 synthesis by gamma-mangostin, a xanthone derivative in mangosteen, in C6 rat glioma cells. 1175 76

The induction of cyclooxygenase (COX)-2 expression has been implicated as a mechanism for the formation of non-hepatic tumors. Recent investigations have demonstrated COX-2 expression in human hepatocellular carcinomas, but little is known about the regulation of hepatocyte COX-2 expression. Employing the adult, rat hepatocyte line RALA255-10G, the effects of cellular transformation or expression of the alcohol-inducible cytochrome P450 2E1 (CYP2E1) on COX-2 expression were examined. Transformed and non-transformed hepatocytes did not express COX-2 by western and northern blot analysis. The tumor promoters phorbol 12-myristate 13-acetate (PMA) and chenodeoxycholic acid (CD) induced COX-2 protein expression in transformed, but not non-transformed cells. CYP2E1-expressing cells lacked constitutive COX-2 expression, and PMA but not CD induced COX-2 in these cells. PMA-treated transformed and CYP2E1-expressing cells expressed functional COX-2 as demonstrated by marked inductions in prostaglandin E(2) synthesis. PMA-induced COX-2 expression in both transformed and CYP2E1-expressing cells resulted from an induction in COX-2 mRNA, and was dependent on extracellular signal-regulated kinase, p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase. The differential induction of COX-2 by PMA in transformed and non-transformed cells could not be explained by differences in NF-kappaB or C/EBPalpha activation. PMA did not induce COX-2 transcriptional activity as determined by transient transfections with a luciferase reporter gene driven by the COX-2 promoter. The data demonstrate that cellular transformation and CYP2E1 expression fail to lead to the induction of COX-2 expression in hepatocytes. However, these conditions do render hepatocytes susceptible to COX-2 induction from tumor promoters by post-transcriptional mechanisms.
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PMID:Induction of cyclooxygenase-2 by tumor promoters in transformed and cytochrome P450 2E1-expressing hepatocytes. 1175 26

The dialogue between trophectoderm cells of the conceptus and epithelial cells of the endometrium is critical to CL maintenance and embryo survival. The signal transduction mechanisms by which bovine interferon (IFN)-tau regulates cyclooxygenase (COX)-2 expression and secretion of prostaglandin F2alpha (PGF2alpha) in bovine endometrial (BEND) cells is examined. Stimulation of Protein Kinase C with a phorbol ester (phorbol 12, 13 dibutyrate [PDBu]) activates COX-2 gene expression and PGF2alpha secretion via the mitogen-activated protein kinase (MAPK) pathway. Interferon-tau attenuates PDBu activation of PGF2alpha secretion, but this inhibitory effect appears to be independent of the MAPK pathway. Embryonic IFN-tau, acting through a Type I IFN receptor, activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway resulting in activation or repression of interferon-stimulated genes. Experimental evidence is provided that IFN-tau regulation of STATs regulates gene expression of COX-2 in a manner that decreases secretion of PGF2alpha. Maternal regulation of the antiluteolytic pathway is discussed relative to the ability of the polyunsaturated fatty acid, eicosapentaenoic (EPA), to decrease endometrial secretion of PGF2alpha and progesterone to increase both conceptus development and IFN-tau secretion.
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PMID:Uterine-conceptus interactions and reproductive failure in cattle. 1176 9

Our recent studies have shown that co-activation of Gq and Gi proteins by 5-hydroxytryptamine (5-HT) and adrenaline show synergism in human platelet aggregation. This study was conducted to examine the mechanism(s) of synergistic interaction of 5-HT and platelet activating factor (PAF) in human platelets. We show that PAF, but not 5-HT, increased platelet aggregation in a concentration-dependent manner. However, low concentrations of 5-HT (2 microM) potentiated platelet aggregation induced by subthreshold concentration of PAF (40 nM) indicating a synergistic interaction between the two agonists and this synergism was blocked by receptor antagonists to either 5-HT or PAF. 5-HT also potentiated the effect of PAF on thromboxane A2 (TXA2) formation and phosphorylation of extracellularly regulated mitogen-activated protein kinases (ERK1/2). The synergism of 5-HT and PAF in platelet aggregation was inhibited by calcium (Ca2+) channel blockers, verapamil and diltiazem, phospholipase C (PLC) inhibitor, U73122, cyclooxygenase (COX) inhibitor, indomethacin, and MEK inhibitor, PD98059. These data suggest that synergistic effect of 5-HT and PAF on human platelet aggregation involves activation of PLC/Ca2+, COX and MAP kinase pathways.
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PMID:Molecular mechanisms involved in human platelet aggregation by synergistic interaction of platelet-activating factor and 5-hydroxytryptamine. 1179 84

Mast cells, platelets, and some macrophages are abundant sources of PGD(2) and its active metabolite 15-deoxy-Delta(12,14)-PGJ(2) (15-d-PGJ(2)). The lipid mediator 15-d-PGJ(2) regulates numerous processes, including adipogenesis, apoptosis, and inflammation. The 15-d-PGJ(2) has been shown to both inhibit as well as induce the production of inflammatory mediators such as TNF-alpha, IL-1beta, and cyclooxygenase, mostly occurring via a nuclear receptor called peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Data concerning the effects of 15-d-PGJ(2) on human T cells and immune regulation are sparse. IL-8, a cytokine with both chemotactic and angiogenic effects, is produced by T lymphocytes following activation. Whether 15-d-PGJ(2) can regulate the production of IL-8 in T cells in unknown. Interestingly, 15-d-PGJ(2) treatment of unstimulated T cells induces cell death. In contrast, in activated human T lymphocytes, 15-d-PGJ(2) does not kill them, but induces the synthesis of IL-8. In this study, we report that 15-d-PGJ(2) induced a significant increase in both IL-8 mRNA and protein from activated human T lymphocytes. The induction of IL-8 by 15-d-PGJ(2) did not occur through the nuclear receptor PPAR-gamma, as synthetic PPAR-gamma agonists did not mimic the IL-8-inducing effects of 15-d-PGJ(2). The mechanism of IL-8 induction was through a mitogen-activated protein kinase and NF-kappaB pathway, as inhibitors of both systems abrogated IL-8 protein induction. Therefore, 15-d-PGJ(2) can act as a potent proinflammatory mediator in activated T cells by inducing the production of IL-8. These findings show the complexity with which 15-d-PGJ(2) regulates T cells by possessing both pro- and anti-inflammatory properties depending on the activation state of the cell. The implications of this research also include that caution is warranted in assigning a solely anti-inflammatory role for 15-d-PGJ(2).
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PMID:15-deoxy-Delta 12,14-PGJ2 induces IL-8 production in human T cells by a mitogen-activated protein kinase pathway. 1180 78


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