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)

We have explored the potential role of redox events in p38 mitogen-activated protein kinase (MAPK) activation and their relevance to the inducible expression of intercellular adhesion molecule-1 (ICAM-1) and heme oxygenase-1 (HO-1) in A549 cells. Tumor necrosis factor-alpha (TNFalpha) and hydrogen peroxide (H2O2) both activated p38, but only TNFalpha activated nuclear factor-kappaB (NF-kappaB). N-Acetyl-L-cysteine (20 mM) inhibited both H2O2- and TNFalpha-induced p38 phosphorylation (14 +/- 7 and 37 +/- 4% of control, respectively). The mitochondrial complex I and III inhibitors, rotenone and antimycin A, and allopurinol partially inhibited H2O2- but not TNFalpha-induced p38 activation. However, rotenone and antimycin A augmented intracellular oxidative stress measured by dichlorofluorescein fluorescence. TNFalpha, but not H2O2, induced ICAM-1 in A549 cells, which was attenuated by a proteasome inhibitor, but not by the p38 MAPK inhibitor SB203580. In contrast, hemin and hemoglobin, but neither TNFalpha nor H2O2, caused efficient HO-1 expression. However, hemin had no effect on p38 activation and SB203580 did not influence hemin-induced HO-1 protein expression. Collectively, these data suggest that p38 is a cytokine- and oxidative stress-responsive pathway in A549 cells. Whereas NF-kappaB appears crucial in ICAM-1 induction, p38 activation itself is not sufficient to confer HO-1 expression and may not be involved in HO-1 and ICAM-1 induction in A549 cells.
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PMID:Redox regulation of p38 MAPK activation and expression of ICAM-1 and heme oxygenase-1 in human alveolar epithelial (A549) cells. 1565 Mar 92

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) may play an important role in atherosclerosis by inducing leukocyte adhesion molecules, such as intercellular and vascular cell adhesion molecule-1 (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]). We hypothesized that eplerenone, a novel selective aldosterone blocker, produces inhibition of LOX-1-mediated adhesion molecules, suppresses mitogen-activated protein (MAP) kinase and its downstream effector p90 ribosomal S6 kinase (p90RSK) through the protein kinase Cepsilon (PKCepsilon) pathway, and improves endothelial function by inhibition of Rho-kinase in the renal cortex of Dahl salt-sensitive hypertensive (DS) and salt-resistant (DR) rats. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of 6 weeks to the left ventricular hypertrophy stage (11 weeks) for 5 weeks. At 11 weeks, expression levels of LOX-1, ICAM-1, VCAM-1, and Rho-kinase were higher in DS rats than in DR rats and were decreased by eplerenone. Similarly, upregulated phosphorylation of PKCepsilon, MAP kinase, and p90RSK in DS rats was also inhibited by eplerenone. In contrast, downregulated endothelial nitric oxide synthase mRNA was increased by eplerenone to a similar degree as after treatment with Y-27632, a selective Rho-kinase inhibitor. Eplerenone administration resulted in significant improvement in glomerulosclerosis (eplerenone 10 mg, -61%; 30 mg, -78%; and 100 mg, -84% versus DS; P<0.01, respectively) and urinary protein (10 mg, -78%; 30 mg, -87%; and 100 mg, -88% versus DS; P<0.01, respectively). These results suggest that the renoprotective effects of eplerenone may be partly caused by inhibition of LOX-1-mediated adhesion molecules and PKCepsilon-MAP kinase-p90RSK pathway, and improvement in endothelial function.
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PMID:Eplerenone shows renoprotective effect by reducing LOX-1-mediated adhesion molecule, PKCepsilon-MAPK-p90RSK, and Rho-kinase pathway. 1571 Jul 85

The role of CD40/CD154 ligation in the upregulation of genes of the proinflammatory nuclear factor-kappaB (NF-kappaB) signal transduction pathway was explored in primary cultures of human renal proximal tubule epithelial cells. Using a cDNA gene array specific for human NF-kappaB signal pathway genes, 38 genes were upregulated at 1 h, and 7 of these genes remained upregulated at 3 h. Of these genes, intercellular adhesion molecule-1 (ICAM-1) was explored in further detail. Quantitative real-time PCR for ICAM-1 mRNA expression confirmed the gene array findings. Western blot analysis and quantitative sandwich-enzyme ELISA confirmed this observation at the protein level. A cell-surface ELISA assay showed that ICAM-1 expression doubled by 48 h of CD154 exposure, and fluorescence-activated cell sorter analysis suggested that both the number of cells expressing ICAM-1 and the expression of ICAM-1 on these cells had increased. A cell adhesion assay using fluorescein-labeled human peripheral mononuclear cells showed that ICAM-1 upregulation resulted in increased mononuclear cell adhesion to the monolayer, which was abrogated by pretreatment of the monolayer with a neutralizing ICAM-1 antibody. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB-203580 but not the extracellular signal-regulated kinase 1/2 inhibitor (PD-98059) nor the protein kinase C inhibitor (calphostin) blunted ICAM-1 expression and mononuclear cell adhesion to the monolayer. We conclude that, in human renal proximal tubule epithelial cells, CD40 activation upregulates ICAM-1 (and other NF-kappaB pathway genes) expression with concomitant enhanced adhesion of mononuclear cells, which is mediated via the p38 MAPK signal transduction pathway.
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PMID:CD40/CD154 ligation induces mononuclear cell adhesion to human renal proximal tubule cells via increased ICAM-1 expression. 1571 10

Inflammation and leukocyte activation/infiltration play a major role in the initiation and progression of cardiovascular diseases including atherosclerosis and heart failure. Acute p38 mitogen-activated protein kinase (MAPK) pathway inhibition attenuates tissue damage and leukocyte accumulation in myocardial ischemia/reperfusion injury, although its effect on the acute phase of leukocyte recruitment has not been elucidated. The purpose of this study was to test the hypothesis that acute treatment of rats with a selective p38 inhibitor, SB-239063, inhibits ischemia/reperfusion-induced leukocyte-endothelial adhesion in vivo. Male Sprague-Dawley rats were treated with either SB-239063 (10 mgkg(-1)), dexamethasone (3 mgkg(-1)) or vehicle 1h prior to ischemia. Postcapillary venules were observed microscopically in exteriorized, superfused cremaster tissue. Leukocytes were fluorescently labeled in vivo using intravenous rhodamine 6G. Leukocyte adhesion, rolling, and rolling velocities were quantitated prior to 30 min ischemia, and at several time points during a 90 min reperfusion period. Ischemia caused a 3-fold increase in adherent leukocytes 5 min following reperfusion, a response that was maintained throughout the monitoring period (90 min) in vehicle-treated animals. SB-239063, at a dose known to inhibit p38 MAPK activity in vivo (10 mgkg(-1)), had no effect on ischemia/reperfusion-induced leukocyte adhesion, the number of rolling leukocytes, rolling velocities during the reperfusion period or adhesion molecule expression (P-, E-selectin, VCAM-1, ICAM-1). In contrast, dexamethasone completely blocked leukocyte adhesion in response to ischemia/reperfusion, and reduced expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). We conclude that p38 MAPK may not play a role in initial leukocyte recruitment in response to ischemia/reperfusion injury, but could affect leukocyte emigration, thereby resulting in increased leukocyte accumulation in ischemic-reperfused tissue.
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PMID:Role of p38 MAP kinase in postcapillary venule leukocyte adhesion induced by ischemia/reperfusion injury. 1574 61

To investigate how respiratory epithelial cells react to an alkylating agent, we exposed human bronchial (BEAS-2B) and alveolar (A549) cells to the nitrogen mustard derivative melphalan. The BEAS-2B cells were highly sensitive to melphalan, as shown by a reduced viability after a 10-min incubation with 300 microM melphalan. The A549 cells were less sensitive and required several hours of exposure to reduce significantly in viability. However, exposure to melphalan also induces activation of intracellular signal transduction pathways, as indicated by phosphorylation of extracellular signal-regulated kinase (ERK1/2) and p38 (proteins belonging to the family of stress-induced mitogen-activated phosphorylated kinases, MAPK) within 5 min, as well as translocation of the transcription factor nuclear factor (NF)-kappaB to the nucleus within 45 min. This early activation was followed by elevated levels of tumor necrosis factor (TNF)-alpha mRNA within 2 h. We also observed increased expression of intercellular adhesion molecule-1 (ICAM-1) on the surface of both cell lines 18 h after exposure to 25 microM melphalan and an increased adhesion of monocytes to the epithelial cells in vitro.In conclusion, we have demonstrated that alkylating compounds not only cause cell death of lung epithelial cells but also activate stress-associated MAPK signal transduction pathways and induce expression of mediators known to participate in the recruitment of inflammatory cells.
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PMID:The nitrogen mustard melphalan activates mitogen-activated phosphorylated kinases (MAPK), nuclear factor-kappaB and inflammatory response in lung epithelial cells. 1602 34

The endothelial lectinlike, oxidatively (ox-) modified LDL receptor LOX-1 is a critical player in the pathogenesis of atherosclerosis and myocardial ischemia. Ox-LDL binding of LOX-1 results in the expression of various adhesion molecules, which attract monocytes to endothelial cells, an initial step in atherogenesis. We wished to examine the role of the ox-LDL/LOX-1 signaling pathway in fibroblasts, which naturally express low levels of LOX-1. Rat cardiac fibroblasts were transfected with either cytomegalovirus (CMV)-LOX-1wt (amino acids [aa] 1 to 273) or CMV-LOX-1(1-261) (an ox-LDL-binding negative mutant, aa 1 to 261) plasmid. Western blots showed that LOX-1 protein expression was increased significantly in cells transfected with CMV-LOX-1wt or CMV-LOX-1(1-261) plasmid (P<0.01 vs control). Fibroblasts transfected with CMV-LOX-1wt showed ox-LDL binding, whereas fibroblasts without transfection and those transfected with CMV-LOX-1(1-261) did not bind ox-LDL. Compared with untransfected cells, ox-LDL treatment (50 microg/mL, 24 hours) markedly induced the expression of the leukocyte adhesion molecules intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM)-1 as well as matrix metalloproteinase (MMP)-1 in cells transfected with CMV-LOX-1wt (P<0.05) but not in cells transfected with CMV-LOX-1(1-261). Concurrently, ox-LDL treatment enhanced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) (P<0.05 vs control) in CMV-LOX-1wt-transfected cells. These data suggest that in cardiac fibroblasts, ox-LDL binds to LOX-1 and activates p38 MAPK, followed by the expression of ICAM-1, VCAM-1, and MMP-1. Thus, fibroblasts transform into an endothelial phenotype on transfection with CMV-LOX-1wt and subsequent exposure to ox-LDL. This study provides a useful model system (plasmid-transfected fibroblasts) to study the molecular biology of LOX-1.
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PMID:Adhesion molecule expression in fibroblasts: alteration in fibroblast biology after transfection with LOX-1 plasmids. 1611 44

Much attention has been paid to the ability of glial cell line-derived neurotrophic factor (GDNF) to protect neurons from neurotoxic insults in the central nervous system (CNS). However, little is known about GDNF action on CNS glia that also can express GDNF receptor systems. In this study, we examined the effects of GDNF on primary rat microglia that function as resident macrophages in the CNS and as the source of proinflammatory mediators upon activation. We found that treatment of primary rat microglia with GDNF had no effect on the secretion of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), but it increased the nitric oxide (NO) production to some extent. In addition, GDNF increased the enzymatic activity of superoxide dismutase (SOD), the gene expression of surface antigen intercellular adhesion molecule-1 (ICAM-1), the production of the integrin alpha5 subunit, and the phagocytotic capability in primary rat microglia. Furthermore, inhibition of mitogen-activated protein kinase (Erk-MAPK) in the mouse microglial cell line BV2 by U0126 indicated that the MAP kinase signaling pathway may be involved in the regulation of NO and integrin alpha5 production by GDNF. In vivo evidence also showed that amoeboid cells with integrin alpha5 or with ED1 immunoreactivity appeared in GDNF-treated spinal cord tissues at the lesion site 1 week post spinal cord injury (SCI). Furthermore, inhibition of Erk-MAPK in the mouse microglial cell line BV2 by U0126 indicated that the MAP kinase signaling pathway may be involved in the regulation of NO and integrin alpha5 production by GDNF. Taken together, our results indicate that GDNF has a positive regulatory effect on microglial activities, such as phagocytosis and the upregulation of adhesion molecules.
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PMID:Regulation of microglial activities by glial cell line derived neurotrophic factor. 1618 94

Hematopoietic cytokines such as interleukin (IL)-3, IL-5, and granulocyte macrophage colony-stimulating factor (GM-CSF) play a fundamental role in eosinophil functions in allergic asthma. The intracellular signal transduction mechanisms of these cytokines regulating the activation of eosinophils have been potential therapeutic targets. We investigated the roles of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-kappaB) in IL-3, IL-5, and GM-CSF-induced adhesion, morphological changes, and subsequence transmigration of human eosinophils. IL-3, IL-5, and GM-CSF could augment the phosphorylation of p38 MAPK and nucleus translocation of NF-kappaB in eosinophils. cDNA expression arrays demonstrated that the gene expression levels of several adhesion molecules including intercellular adhesion molecule-1 (ICAM-1), alpha6, beta2 integrin (CD18), and CD44 were upregulated by these cytokines. Results from functional assays showed that adhesion of eosinophils onto airway epithelial cells was enhanced after IL-3 and IL-5 but not GM-CSF stimulation. These cytokines could markedly induce shape change and augment the transmigration of eosinophils. Moreover, administration of either p38 MAPK inhibitor, SB 203580, or proteasome inhibitor, N-cbz-Leu-Leu-leucinal (MG-132), could inhibit the cytokine-induced adhesion, shape change, and transmigration of eosinophils. Together, our findings suggest that IL-3, IL-5, and GM-CSF regulated the adhesion and chemotaxis of human eosinophils through shared signaling pathways involving both p38 MAPK and NF-kappaB. Our results therefore shed light on the further development of more effective agents for allergic and inflammatory diseases.
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PMID:Interleukin-3, -5, and granulocyte macrophage colony-stimulating factor induce adhesion and chemotaxis of human eosinophils via p38 mitogen-activated protein kinase and nuclear factor kappaB. 1623 50

Piceatannol is an anti-inflammatory and anti-proliferative plant-derived stilbene. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme to activate by various phytochemicals. In this study, we examined the ability of piceatannol to upregulate HO-1 expression in endothelial cells. We found piceatannol at micromolar (10-50 microM) concentrations dramatically increased HO-1 protein levels in a time-dependent manner. Piceatannol was similarly potent in the induction of HO-1 as hemin, arsenate, and 15d-PGJ2, and was more potent than some other phytochemicals including curcumin, EGCG, baicalein, and quercetin. In contrast, the similar chemical structure compounds, trans-stilbene, stilbene oxide, and resveratrol had no HO-1-inducing effects, suggesting a critical role for the hydroxyl groups in HO-1 induction. No cytotoxicity and superoxide production was observed after 10-50 microM piceatannol treatments. Piceatannol-mediated HO-1 induction was abrogated in the presence of N-acetylcysteine and glutathione, but not by other antioxidants. Induction of HO-1 by piceatannol was further enhanced by using buthionine sulfoximine. In addition, we determined that tyrosine kinase was involved in the induction of HO-1 by using tyrosine kinase inhibitors, herbimycin A, erbstatin, and genistein; in contrast, no significant changes in the pretreatment of PI3 kinase or MAP kinase inhibitors was determined. HO-1 induction was blocked by the protein kinase C inhibitors calphostin C, rottlerin, and long PMA pretreatment, whereas conventional PKC inhibitors, Go6976, and Ca2+ chelator BAPTA/AM, had no effect. Elevated HO-1 protein levels were associated with the inhibition of tumor necrosis factor-alpha (TNFalpha)-induced intercellular adhesion molecule-1 (ICAM-1) expression. Treating ECs with zinc protoporphyrin, an HO-1 inhibito blocked the anti-inflammatory effect of piceatannol. In summary, this study identified piceatannol as a novel phytochemical inducer of HO-1 expression and identified the mechanisms involved in this process.
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PMID:Piceatannol upregulates endothelial heme oxygenase-1 expression via novel protein kinase C and tyrosine kinase pathways. 1624 36

Matrix metalloproteinase-1 (MMP-1) plays an important role in the degradation of collagen in inflammatory diseases. The aim of this study was to investigate the cellular expression of MMP-1 and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), in gingival fibroblasts co-cultured with monocytes and the possible mediating role of intercellular adhesion molecule-1 (ICAM-1). In co-cultures, the expression of MMP-1 and TIMP-1 increased in fibroblasts, but not in monocytes, although the number of MMP-1+ and TIMP-1+ adhered monocytes increased. Moreover, ICAM-1 expression in both fibroblasts and adhered monocytes increased. In the presence of an anti-ICAM-1 antibody, the expression of MMP-1 in fibroblasts decreased whereas the number of TIMP-1+ adhered monocytes increased. The p38 MAPK inhibitor SB203580 reduced MMP-1 expression in fibroblasts, as well as ICAM-1 expression in both fibroblasts and adhered monocytes. The results suggest that co-culture with monocytes enhances cellular expression of MMP-1 and TIMP-1 in gingival fibroblasts, and that the increased MMP-1 expression, in contrast to TIMP-1, is partly mediated by the adhesion molecule ICAM-1 and the p38 MAPK signal pathway.
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PMID:Cell expression of MMP-1 and TIMP-1 in co-cultures of human gingival fibroblasts and monocytes: the involvement of ICAM-1. 1628 11


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