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)

Lipopolysaccharide is a major constituent of the outer membrane of Gram-negative bacteria. It activates monocytes and macrophages to produce cytokines such as tumor necrosis factor-alpha and interleukins IL-1beta and IL-6. These cytokines appear to be responsible for the neurotoxicity observed in peripheral nervous system inflammatory disease. It has been reported that, in the central nervous system, the expression level of intercellular adhesion molecule-1 (ICAM-1) was dramatically upregulated in response to LPS, as well as many inflammatory cytokines. ICAM-1 contributes to multiple processes seen in central nervous system inflammatory disease, for example migration of leukocytes to inflammatory sites, and adhesion of polymorphonuclear cells and monocytes to central nervous system cells. In the present study, we found that lipopolysacharide evoked ICAM-1 mRNA and protein expression early at 1 h post-injection, and the most significant increase was seen at 4 h. Immunofluorescence double-labeling suggested that most of the ICAM-1-positive staining was located in Schwann cells. Using Schwann cell cultures, we demonstrated that ICAM-1 expression in Schwann cells is regulated by mitogen-activated protein kinases, especially the p38 and stress-activated protein kinase/c-Jun N-terminal kinase pathways. Thus, it is thought that upregulation of ICAM-1 expression in Schwann cells may be important for host defenses after peripheral nervous system injury, and reducing the biosynthesis of ICAM-1 and other cytokines by blocking the cell signal pathway might provide a new strategy against inflammatory and immune reaction after peripheral nerve injury.
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PMID:Lipopolysaccharide-evoked activation of p38 and JNK leads to an increase in ICAM-1 expression in Schwann cells of sciatic nerves. 1865 90

Activation of the CD40 receptor by its cognate ligand, CD154, results in interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) production and increased intercellular adhesion molecule-1 (ICAM-1) expression in proximal tubule cells (PTCs). The independent role of these two proinflammatory chemokines, IL-8 and MCP-1, in inciting an inflammatory response in PTCs was explored. Exposure of primary cultures of human renal PTCs to recombinant IL-8 and MCP-1 resulted in increased ICAM-1 expression measured by quantitative real-time PCR, but confirmed only for IL-8 by immunoblot. The mechanism of action of IL-8 was explored in further detail. Immunohistochemistry identified both the CXCR-1 and CXCR-2 receptors, confirmed by RT-PCR, immunoprecipitation, immunoblot, and FACS analysis. IL-8 increased ICAM-1 expression only via the CXCR-1 receptor, which in turn resulted in activation of the p38 mitogen-activated protein kinase (MAPK) pathway; neither the extracellular signal-related kinase (ERK) 1/2 MAPK pathway nor the stress-activated protein kinase (SAPK)/c-Jun NH(2) terminal kinase (JNK) pathway was involved. CD154/CD40-mediated ICAM-1 upregulation was not affected by preincubation of monolayers with the CXCR-1 blocking antibody, indicating that ICAM-1 expression occurs independent of CD154-mediated IL-8 production. Coincubation of monolayers with both CD154 and IL-8 resulted in a greater ICAM-1 response than either compound alone. We conclude that in human renal PTCs, IL-8 upregulates ICAM-1 production by engaging the CXCR-1 receptor and p38 MAPK signaling pathway. This cascade of events is independent of CD40/CD154-mediated IL-8 stimulation and ICAM-1 production and serves to amplify the inflammatory response.
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PMID:IL-8 amplifies CD40/CD154-mediated ICAM-1 production via the CXCR-1 receptor and p38-MAPK pathway in human renal proximal tubule cells. 1866 84

Toxicologic and epidemiologic studies have linked benzo[a]pyrene (B[a]P) exposure with cardiovascular diseases such as atherosclerosis. The mechanisms of action leading to these diseases have not been fully understood. One key step in the development of atherosclerosis is vascular endothelial dysfunction, which is characterized by increased adhesiveness. To determine if B[a]P could lead to increased endothelial adhesiveness, the effects of B[a]P on human endothelial cell intercellular adhesion molecule-1 (ICAM-1) expression was investigated. B[a]P was able to increase ICAM-1 protein only after pretreatment with the aryl hydrocarbon receptor (AhR) agonist beta-naphthoflavone (beta-NF). Knockdown of AhR by siRNA or treatment with AhR antagonist alpha-naphthoflavone (alpha-NF) eliminated the induction of ICAM-1 from B[a]P, confirming the necessity of AhR in this process. Likewise, B[a]P only increased monocyte adhesion to the vascular endothelium when cells were pretreated with beta-NF. Experiments were done to define a signaling mechanism. B[a]P increased phosphorylation of MEK and p38-MAPK, and inhibitors to these proteins blunted the ICAM-1 induction. B[a]P was also able to increase AP-1 DNA binding and phosphorylation of cJun. Phosphorylation of cJun was disrupted by MEK and p38-MAPK inhibitors linking the signaling cascade. Finally, the importance of membrane microdomains, caveolae, was demonstrated by knockdown of the structural protein caveolin-1. Disruption of caveolae eliminated the B[a]P-induced ICAM-1 expression. These data suggest a possible pro-inflammatory mechanism of action of B[a]P involving caveolae, leading to increased vascular endothelial adhesiveness, and this inflammation may be a critical step in the development of B[a]P-induced atherosclerosis.
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PMID:Benzo[a]pyrene induces intercellular adhesion molecule-1 through a caveolae and aryl hydrocarbon receptor mediated pathway. 1867 94

E-selectin binding to P-selectin glycoprotein ligand-1 (PSGL-1) can activate the beta(2) integrin lymphocyte function-associated antigen-1 by signaling through spleen tyrosine kinase (Syk). This signaling is independent of G alpha(i)-protein-coupled receptors, results in slow rolling, and promotes neutrophil recruitment to sites of inflammation. However, the signaling pathways linking E-selectin engagement of PSGL-1 to Syk activation are unknown. To test the role of Src family kinases and immunoreceptor tyrosine-based activating motif (ITAM)-containing adaptor proteins, we used different gene-deficient mice in flow chamber, intravital microscopy, and peritonitis studies. E-selectin-mediated phosphorylation of Syk and slow rolling was abolished in neutrophils from fgr(-/-) or hck(-/-) lyn(-/-) fgr(-/-) mice. Neutrophils from Tyrobp(-/-) Fcrg(-/-) mice lacking both DAP12 and FcRgamma were incapable of sustaining slow neutrophil rolling on E-selectin and intercellular adhesion molecule-1 and were unable to phosphorylate Syk and p38 MAPK. This defect was confirmed in vivo by using mixed chimeric mice. G alpha(i)-independent neutrophil recruitment into the inflamed peritoneal cavity was sharply suppressed in Tyrobp(-/-) Fcrg(-/-) mice. Our data demonstrate that an ITAM-dependent pathway involving the Src-family kinase Fgr and the ITAM-containing adaptor proteins DAP12 and FcRgamma is involved in the initial signaling events downstream of PSGL-1 that are required to initiate neutrophil slow rolling.
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PMID:PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcR gamma to induce slow leukocyte rolling. 1879 38

Epidemiologic studies have shown a strong association between cigarette smoking and cardiovascular diseases. Various oxidative species and free radicals are produced during cigarette smoking and these lead to endothelial dysfunction and inflammation. Expression of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), E-selectin, and vascular cell adhesion molecule-1, and adhesion of leukocytes are present in atherosclerosis. We showed previously that a nonfractionated cigarette smoke extract (CSE) induces surface expression of ICAM-1 and E-selectin in human umbilical vein endothelial cells (HUVEC). We then investigated the role of the MAPKs (ERK1/2, JNK, and p38) and AP-1 and the role of actin cytoskeleton reorganization in the CSE-induced expression of ICAM-1 and E-selectin. Western blot analysis showed that CSE treatment rapidly and significantly caused phosphorylation of JNK and ERK1/2 but not of p38. Cytochalasin D (an actin filament disruptor) partially inhibited CSE-induced ICAM-1 and E-selectin surface expression. However, inhibitors of ERK1/2 (PD98059) and JNK (SP600125) did not attenuate the CSE-induced ICAM-1 and E-selectin surface expression. The results of electrophoretic mobility shift assay showed that CSE enhanced AP-1 binding activity. Therefore, CSE activated AP-1 and upregulated ICAM-1 and E-selectin surface expression in HUVEC seem to be via an MAPK-independent pathway. Moreover, the dynamic reorganization of the actin cytoskeleton seems to be required for the CSE-induced surface expression of ICAM-1 and E-selectin.
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PMID:Cigarette smoke extract induces expression of cell adhesion molecules in HUVEC via actin filament reorganization. 1910 7

Recent studies have indicated that bone marrow-derived mesenchymal stem cells (BMSCs) have the capacity of migrating towards gliomas. However, few data are available about the molecular mechanism responsible for this migratory capacity. The aim of our study was to investigate the role of platelet-derived growth factor BB (PDGFBB) in the migration of BMSCs towards C6 glioma and evaluate the effect of PDGFBB on the migrating capacity and intercellular adhesion molecule-1 (ICAM-1) expression of BMSCs. The chemokinetic activity of BMSCs in response to C6 glioma-conditioned medium and recombinant rat PDGFBB was analyzed by in vitro migration assay. The effect of PDGFBB on the expression of ICAM-1 was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. Our data showed that C6 glioma-conditioned medium significantly increased the migration of BMSCs, which could be partially blocked by a PDGFBB neutralizing antibody. Recombinant rat PDGFBB enhanced the migration of BMSCs in a concentration-dependent way from 5 to 50ng/ml. Moreover, RT-PCR and immunofluorescence showed that 12h of 20ng/ml PDGFBB incubation could up-regulate the ICAM-1 expression of BMSCs. Our data also revealed that SB203580, an inhibitor of p38 mitogen-activated protein kinase (MAPK), significantly decreased the PDGFBB-induced migration and ICAM-1 expression of BMSCs. These results demonstrate that PDGFBB contributes to the migration of BMSCs towards C6 glioma and up-regulates the expression of ICAM-1, and that p38MAPK is an important signaling molecule correlating with the signal transduction of PDGFBB-induced migration and ICAM-1 expression of BMSCs.
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PMID:Platelet-derived growth factor BB promotes the migration of bone marrow-derived mesenchymal stem cells towards C6 glioma and up-regulates the expression of intracellular adhesion molecule-1. 1913 16

We previously demonstrated that fibrinogen (Fg) binding to the vascular endothelial intercellular adhesion molecule-1 (ICAM-1) leads to microvascular constriction in vivo and in vitro. Although a role of endothelin-1 (ET-1) in this Fg-induced vasoconstriction was suggested, the mechanism of action was not clear. In the current study, we tested the hypothesis that Fg-induced vasoconstriction results from ET-1 production by vascular endothelial cells (EC) and is mediated by activation of extracellular signal-regulated kinase -1/2 (ERK-1/2). Confluent, rat heart microvascular endothelial cells (RHMECs) were treated with one of the following: Fg (2 or 4 mg/ml), Fg (4 mg/ml) with ERK-1/2 kinase inhibitors (PD-98059 or U-0126), Fg (4 mg/ml) with an antibody against ICAM-1, or medium alone for 45 min. The amount of ET-1 formed and the concentration of released von Willebrand factor (vWF) in the cell culture medium were measured by ELISAs. Fg-induced exocytosis of Weibel-Palade bodies (WPBs) was assessed by immunocytochemistry. Phosphorylation of ERK-1/2 was detected by Western blot analysis. Fg caused a dose-dependent increase in ET-1 formation and release of vWF from the RHMECs. This Fg-induced increase in ET-1 production was inhibited by specific ERK-1/2 kinase inhibitors and by anti-ICAM-1 antibody. Immunocytochemical staining showed that an increase in Fg concentration enhanced exocytosis of WPBs in ECs. A specific endothelin type B receptor blocker, BQ-788, attenuated the enhanced phosphorylation of ERK-1/2 in ECs caused by increased Fg content in the culture medium. The presence of an endothelin converting enzyme inhibitor, SM-19712, slightly decreased Fg-induced phosphorylation of ERK-1/2, but inhibited production of Fg-induced ET-1 production. These results suggest that Fg-induced vasoconstriction may be mediated, in part, by activation of ERK-1/2 signaling and increased production of ET-1 that further increases EC ERK-1/2 signaling. Thus, an increased content of Fg may enhance vasoconstriction through increased production of ET-1.
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PMID:Fibrinogen-induced endothelin-1 production from endothelial cells. 1919 66

Increasing evidence demonstrates that interleukin (IL)-32 is a pro-inflammatory cytokine, inducing IL-1alpha, IL-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and chemokines via nuclear factor (NF)-kappaB, p38 mitogen-activated protein kinase (MAPK), and activating protein (AP)-1 activation. Here we report that IL-32 is expressed and is also functional in human vascular endothelial cells (EC) of various origins. Compared with primary blood monocytes, high levels of IL-32 are constitutively produced in human umbilical vein EC (HUVEC), aortic macrovascular EC, and cardiac as well as pulmonary microvascular EC. At concentrations as low as 0.1 ng/ml, IL-1beta stimulated IL-32 up to 15-fold over constitutive levels, whereas 10 ng/ml of TNFalpha or 100 ng/ml of lipopolysaccharide (LPS) were required to induce similar quantities of IL-32. IL-1beta-induced IL-32 was reduced by inhibition of the IkappaB kinase-beta/NF-kappaB and ERK pathways. In addition to IL-1beta, pro-coagulant concentrations of thrombin or fresh platelets increased IL-32 protein up to 6-fold. IL-1beta and thrombin induced an isoform-switch in steady-state mRNA levels from IL-32alpha/gamma to beta/epsilon. Adult EC responded in a similar fashion. To prove functionality, we silenced endogenous IL-32 with siRNA, decreasing intracellular IL-32 protein levels by 86%. The knockdown of IL-32 resulted in reduction of constitutive as well as IL-1beta-induced intercellular adhesion molecule-1 (ICAM-1) (of 55% and 54%, respectively), IL-1alpha (of 62% and 43%), IL-6 (of 53% and 43%), and IL-8 (of 46% and 42%). In contrast, the anti-inflammatory/anti-coagulant CD141/thrombomodulin increased markedly when IL-32 was silenced. This study introduces IL-32 as a critical regulator of endothelial function, expanding the properties of this cytokine relevant to coagulation, endothelial inflammation, and atherosclerosis.
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PMID:IL-32-dependent effects of IL-1beta on endothelial cell functions. 1922 41

We here investigated the functional effect of withaferin A on airway inflammation and its action mechanism. Withaferin A inhibited the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human lung epithelial A549 cells stimulated with tumor necrosis factor-alpha (TNF-alpha), resulting in the suppression of leukocyte adhesion to lung epithelial A549 cells. In addition, withaferin A inhibited TNF-alpha-induced expression of adhesion molecules (ICAM-1 and VCAM-1) protein and mRNA in a dose-dependent manner. Withaferin A prevented DNA binding activity of nuclear factor-kappaB (NF-kappaB) and nuclear translocation of NF-kappaB. It also inhibited phosphorylation of Akt and extracellular signal-regulated kinase (ERK), which are upstream in the regulation of adhesion molecules by TNF-alpha. Furthermore, withaferin A inhibited U937 monocyte adhesion to A549 cells stimulated by TNF-alpha, suggesting that it may inhibit the binding of these cells by regulating the expression of critical adhesion molecules by TNF-alpha. Taken together, these results suggest that withaferin A inhibits cell adhesion through inhibition of ICAM-1 and VCAM-1 expression, at least in part, by blocking Akt and down-regulating NF-kappaB activity.
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PMID:Withaferin A inhibits tumor necrosis factor-alpha-induced expression of cell adhesion molecules by inactivation of Akt and NF-kappaB in human pulmonary epithelial cells. 1923 58

We aimed to investigate the effect of tumor necrosis factor-alpha (TNF-alpha) on the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the migration ability of mesenchymal stem cells (MSCs) in the context of wound healing. We also explored the role of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) signaling pathways in the migration of MSCs. MSCs were isolated from the bone marrow and cultured. Immunocytochemistry, Western blotting, and reverse transcription-polymerase chain reaction were used to observe the effect of TNF-alpha on the expression of ICAM-1 and VCAM-1 in MSCs. The chemotaxis effect of TNF-alpha on MSCs was investigated by the trans-well system and the inhibition effect of TNF-alpha using its antibody. Western blotting analysis was used to observe the activation of JAK-STAT and mitogen-activated protein kinase signaling pathways, and ERK was inhibited with PD98059 and p38 with SB203580 to observe the effect of TNF-alpha on MSC migration and ICAM-1 expression. The expression of ICAM-1 could be up-regulated by 50 microg/L TNF-alpha (p<0.05), whereas that of VCAM-1 remained unchanged (p>0.05). Also, TNF-alpha showed a chemotaxis effect by enhancing the migration ability of MSCs (p<0.05). TNF-alpha at 50 microg/L increased the expression of phospho-ERK and phospho-p38, and SB203580, but not PD98059, could suppress the chemotaxis effect and up-regulation of ICAM-1 induced by TNF-alpha in MSCs (p<0.05). Thus, TNF-alpha could up-regulate the expression of ICAM-1 in MSCs and enhance the cells' migration ability, and the p38 signaling pathway might be involved in the TNF-alpha-induced migration ability for a role in wound repair and regeneration.
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PMID:Migration of bone marrow-derived mesenchymal stem cells induced by tumor necrosis factor-alpha and its possible role in wound healing. 1932 Aug 86


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