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)

Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), a member of the TNF family, is a multi-functional cytokine that regulates cellular proliferation, angiogenesis, inflammation and apoptosis. In this study, we investigated TWEAK expression in periodontally diseased tissues and the effect of TWEAK on human gingival fibroblasts (HGF). Reverse transcription-polymerase chain reaction (RT-PCR) analysis and immunohistochemistry revealed that TWEAK and the TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), mRNA and protein were expressed in periodontally diseased tissues. HGF expressed Fn14 and produced interleukin (IL)-8 and vascular endothelial growth factor (VEGF) production upon TWEAK stimulation in a dose-dependent manner. The IL-8 and VEGF production induced by TWEAK was augmented synergistically by simultaneous stimulation with transforming growth factor (TGF)-beta1 or IL-1beta. IL-1beta and TGF-beta1 enhanced Fn14 expression in a dose-dependent manner. Moreover, TWEAK induced intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression on HGF in a dose-dependent manner. The ICAM-1 expression induced by TWEAK was augmented by TGF-beta1. On the other hand, the TWEAK-induced VCAM-1 expression was inhibited by TGF-beta1. Phosphatidylinositol 3-kinase (PI3K) and nuclear factor-kappaB (NF-kappaB) inhibitor inhibit both ICAM-1 and VCAM-1 expression induced by TWEAK. However, mitogen-activated protein kinase (MEK) and c-Jun NH2-terminal kinase (JNK) inhibitor enhanced only VCAM-1 expression on HGF. These results suggest that TWEAK may be involved in the pathophysiology of periodontal disease. Moreover, in combination with IL-1beta or TGF-beta1, TWEAK may be related to the exacerbation of periodontal disease to induce proinflammatory cytokines and adherent molecules by HGF.
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PMID:Proinflammatory effects of tumour necrosis factor-like weak inducer of apoptosis (TWEAK) on human gingival fibroblasts. 1710 Jul 76

The airway epithelium plays an active role in acute lung inflammation by producing chemotactic factors and by expressing cell adhesion molecules involved in the migration of leucocytes to extravascular spaces. We have reported previously that neutrophil migration to airways can be down-modulated by exogenously administered vitamin E (alpha-tocopherol). The mechanism for this effect is not well understood, however. The action of alpha-tocopherol was investigated in human alveolar type II and bronchial epithelial cells stimulated with tumour necrosis factor-alpha. Treatment of alveolar epithelial cells with alpha-tocopherol resulted in down-regulated cell surface expression of intercellular adhesion molecule-1 (ICAM-1). On bronchial epithelial cells, both ICAM-1 and vascular adhesion molecule-1 were decreased, leading to diminished adherence of leucocytes to the cells. The production of the neutrophil chemoattractant interleukin-8 was attenuated in both alveolar and bronchial cells. These effects were preceded by reduced activation of the mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinase (ERK1/2) and p38, as well as down-regulation of nuclear factor-kappaB. Comparing the effects of alpha-tocopherol with that of specific inhibitors of MAPK and protein kinase C (PKC) revealed that effects appear to be partly independent of PKC inhibition. These results implicate the anti-inflammatory action of alpha-tocopherol in addition to its anti-oxidant properties.
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PMID:Vitamin E down-modulates mitogen-activated protein kinases, nuclear factor-kappaB and inflammatory responses in lung epithelial cells. 1722 79

Paeonol (2'-hydroxy-4'-methoxyacetophenone), the main active compound of the traditionally used Chinese herb Paeonia lactiflora Pallas, has anti-inflammatory, antioxidant and cardiovascular protective activities. We studied how the levels of intercellular adhesion molecule-1 (ICAM-1), one of the key molecules in the development of atherosclerosis, might be affected by paeonol in tumor necrosis factor-alpha (TNF-alpha)-activated human umbilical vein endothelial cells (HUVECs). Paeonol concentration-dependently inhibited the production of ICAM-1; it inhibited nuclear factor-kappaB (NF-kappaB) p65 translocation into the nucleus and the phosphorylation of inhibitory factor kappaBalpha (IkappaBalpha). It also blocked the TNF-alpha-induced phosphorylation of p38 and extracellular signal-regulated kinase (ERK), which are involved in regulating ICAM-1 production by TNF-alpha. Paeonol inhibited U937 monocyte adhesion to HUVECs stimulated by TNF-alpha, suggesting that it may inhibit the binding of monocytes to endothelium by regulating the production of critical adhesion molecules by TNF-alpha. The inhibitory effect of paeonol on ICAM-1 production might be mediated by inhibiting p38, ERK and NF-kappaB signaling pathways, which are involved in TNF-alpha-induced ICAM-1 production. Thus, paeonol may be beneficial in the treatment of cardiovascular disorders such as atherosclerosis.
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PMID:Paeonol suppresses intercellular adhesion molecule-1 expression in tumor necrosis factor-alpha-stimulated human umbilical vein endothelial cells by blocking p38, ERK and nuclear factor-kappaB signaling pathways. 1727 92

Substance P, a pro-inflammatory neuropeptide, is released from cardiac peptidergic nerves under conditions like ischemia but whether it modulates inflammatory processes in the heart remains unexplored. This study demonstrates for the first time that substance P augments the production of the soluble form of intercellular adhesion molecule-1, sICAM-1, by adult rat cardiac fibroblasts. However, RT-PCR showed no concomitant increase in ICAM-1 transcript levels, suggesting that the increase in sICAM-1 may involve post-transcriptional/translational mechanisms. Use of pharmacological inhibitors revealed that the stimulatory effect of substance P on sICAM-1 production is mediated by p42/44 MAPK and protein kinase C. Preliminary experiments also showed that the neuropeptide stimulates the production of prostaglandin E(2) by cardiac fibroblasts. The findings support the postulation that substance P may modulate multiple inflammatory responses within the myocardium through release of pro-inflammatory mediators from resident fibroblasts.
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PMID:Substance P enhances soluble ICAM-1 release from adult rat cardiac fibroblasts by a p42/44 MAPK- and PKC-mediated mechanism. 1733 2

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is emerging as a key contributor for endothelial dysfunction associated with inflammation. Statins can inhibit vascular inflammatory reaction and improve endothelial function. The aim of this study was to investigate in human endothelial cells the signaling pathways of ADMA-induced inflammatory reaction and potential inhibitory effects of simvastatin. Endothelial cells were cultured and used for all of the studies. Tumor necrosis factor-alpha(TNF-alpha) and soluble intercellular adhesion molecule-1 (sICAM-1) were determined by enzyme-linked immunosorbent assay. Nuclear factor-kappaB (NF-kappaB) was assayed by electrophoretic mobility shift assay. The activation of mitogen-activated protein kinases (MAPKs), including p38 MAPK and extracellular signal-related kinase (ERK(1/2)), were characterized by Western blot analysis. Treatment with ADMA (3-30 micromol/L) increased the concentration of sICAM-1 in a dose-dependent manner. ADMA (30 micromol/L) significantly enhanced the concentrations of TNF-alpha and sICAM-1, the activity of NF-kappaB and the phosphorylation of p38 MAPK and ERK(1/2). The increased secretion of TNF-alpha and sICAM-1 and the increased activity of NF-kappaB by ADMA were altered by SB203580 (5 micromol/L) or PD98059 (20 micromol/L), but not by LY294002 (20 micromol/L). Simvastatin (0.1, 0.5, or 2.5 micromol/L) markedly inhibited the elevated concentrations of TNF-alpha and sICAM-1, the activity of NF-kappaB, and the phosphorylation of p38 MAPK and ERK(1/2) induced by ADMA. Simvastatin inhibited ADMA-induced inflammatory reaction by p38 MAPK and ERK(1/2) pathways in cultured endothelial cells.
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PMID:The inhibitory effect of simvastatin on the ADMA-induced inflammatory reaction is mediated by MAPK pathways in endothelial cells. 1746 46

We investigated the regulatory role of glutathione in tumor necrosis factor-alpha (TNF-alpha)-induced vascular endothelial dysfunction as evaluated by using vascular endothelial adhesion molecule expression and monocyte-endothelial monolayer binding. Since TNF-alpha induces various biological effects on vascular cells, TNF-alpha dosage could be a determinant factor directing vascular cells into different biological fates. Based on the adhesion molecule expression patterns responding to different TNF-alpha concentrations, we adopted the lower TNF-alpha (0.2 ng/ml) to rule out the possible involvement of other TNF-alpha-induced biological effects. Inhibition of glutathione synthesis by l-buthionine-(S,R)-sulfoximine (BSO) resulted in down-regulations of the TNF-alpha-induced adhesion molecule expression and monocyte-endothelial monolayer binding. BSO attenuated the TNF-alpha-induced nuclear factor-kappaB (NF-kappaB) activation, however, with no detectable effect on AP-1 and its related mitogen-activated protein kinases (MAPKs). Deletion of an AP-1 binding site in intercellular adhesion molecule-1 (ICAM-1) promoter totally abolished its constitutive promoter activity and its responsiveness to TNF-alpha. Inhibition of ERK, JNK, or NF-kappaB attenuates TNF-alpha-induced ICAM-1 promoter activation and monocyte-endothelial monolayer binding. Our study indicates that TNF-alpha induces adhesion molecule expression and monocyte-endothelial monolayer binding mainly via activation of NF-kappaB in a glutathione-sensitive manner. We also demonstrated that intracellular glutathione does not modulate the activation of MAPKs and/or their downstream AP-1 induced by lower TNF-alpha. Although AP-1 activation by the lower TNF-alpha was not detected in our systems, we could not rule out the possible involvement of transiently activated MAPKs/AP-1 in the regulation of TNF-alpha-induced adhesion molecule expression.
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PMID:Glutathione regulation of redox-sensitive signals in tumor necrosis factor-alpha-induced vascular endothelial dysfunction. 1746 21

Ginsenosides, the main component of Panax ginseng, have been known for the anti-inflammatory and anti-proliferative activities. In this study, we investigated the molecular mechanisms responsible for the anti-inflammatory effects of ginsenosides on activated astroglial cells. Among 13 different ginsenosides, intestinal bacterial metabolites Rh(2) and compound K (C-K) showed a significant inhibitory effect on tumor necrosis factor-alpha (TNF-alpha)-induced expression of intercellular adhesion molecule-1 in human astroglial cells. Pretreatment with C-K or Rh(2) suppressed TNF-alpha-induced phosphorylation of IkappaBalpha kinase and the subsequent phosphorylation and degradation of IkappaBalpha. Additionally, the same treatment inhibited TNF-alpha-induced phosphorylation of MKK4 and the subsequent activation of the JNK-AP-1 pathway. The inhibitory effect of ginsenosides on TNF-alpha-induced activation of the NF-kappaB and JNK pathways was not observed in human monocytic U937 cells. These results collectively indicate that ginsenoside metabolites C-K and Rh(2) exert anti-inflammatory effects by the inhibition of both NF-kappaB and JNK pathways in a cell-specific manner.
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PMID:Ginsenosides compound K and Rh(2) inhibit tumor necrosis factor-alpha-induced activation of the NF-kappaB and JNK pathways in human astroglial cells. 1754 55

Fibrinogen deposition in the vessel wall represents an independent atherogenic risk factor. In Boyden-chamber assays, fibrinogen concentration-dependently (1-100 microM) induced migration of human vascular smooth muscle cells (SMC). This was inhibited by antibodies to intercellular adhesion molecule-1 (ICAM-1, 10 microg/ml), and by inhibitors of PI3-kinase (LY294002, 10 microM) and MAPK (mitogen-activated protein kinase) p38 (SB203580, 10 microM). The MEK (MAP kinase kinase) inhibitor PD98059 (10 muM) and the GPIIb/IIIa antagonist abciximab (10 mug/ml) had no effect. ICAM-1 antibodies inhibited fibrinogen-induced Akt and p38 phosphorylation. Thus fibrinogen stimulates human SMC migration through binding to ICAM-1 and activation of Akt and p38.
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PMID:ICAM-1 and p38 MAPK mediate fibrinogen-induced migration of human vascular smooth muscle cells. 1790 46

The house dust mite (HDM) is considered to be the most common indoor allergen associated with bronchial asthma. In this study, we investigated whether crude extract of the HDM Dermatophagoides farinae could activate human eosinophilic leukemic cells (EoL-1) to induce upregulation of cell-surface adhesion molecules. When EoL-1 cells were incubated with D. farinae extract, expression of intercellular adhesion molecule-1 (ICAM-1) significantly increased on the cell surfaces compared to cells incubated with medium alone. In contrast, surface expression of CD11b and CD49d in EoL-1 cells was not affected by D. farinae extract. In addition, pretreatment of cells with NF-kappaB inhibitor (MG-132) or JNK inhibitor (SP600125) significantly inhibited ICAM-1 expression promoted by HDM extract. However, neither p38 MAP kinase inhibitor nor MEK inhibitor prevented HDM-induced ICAM-1 expression in EoL-1 cells. These results suggest that crude extract of D. farinae induces ICAM-1 expression in EoL-1 cells through signaling pathways involving both NF-kappaB and JNK.
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PMID:House dust mite induces expression of intercellular adhesion molecule-1 in EoL-1 human eosinophilic leukemic cells. 1798 28

We assessed the role of nitric oxide (NO) and the kinin B2 receptor in mediating tissue kallikrein's actions in intramyocardial inflammation and cardiac remodeling after ischemia/reperfusion (I/R) injury. Adenovirus carrying the human tissue kallikrein gene was delivered locally into rat hearts 4 days prior to 30-minute ischemia followed by 24-hour or 7-day reperfusion with or without administration of icatibant, a kinin B2 receptor antagonist, or N(omega)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. Kallikrein gene delivery improved cardiac contractility and diastolic function, reduced infarct size at 1 day after I/R without affecting mean arterial pressure. Kallikrein treatment reduced macrophage/monocyte and neutrophil accumulation in the infarcted myocardium in association with reduced intercellular adhesion molecule-1 levels. Kallikrein increased cardiac endothelial nitric oxide synthase phosphorylation and NO levels and decreased superoxide formation, TGF-beta1 levels and Smad2 phosphorylation. Furthermore, kallikrein reduced I/R-induced JNK, p38MAPK, IkappaB-alpha phosphorylation and nuclear NF-kappaB activation. In addition, kallikrein improved cardiac performance, reduced infarct size and prevented ventricular wall thinning at 7 days after I/R. The effects of kallikrein on cardiac function, inflammation and signaling mediators were all blocked by icatibant and L-NAME. These results indicate that tissue kallikrein through kinin B2 receptor and NO formation improves cardiac function, prevents inflammation and limits left ventricular remodeling after myocardial I/R by suppression of oxidative stress, TGF-beta1/Smad2 and JNK/p38MAPK signaling pathways and NF-kappaB activation.
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PMID:Nitric oxide mediates cardiac protection of tissue kallikrein by reducing inflammation and ventricular remodeling after myocardial ischemia/reperfusion. 1806 96


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