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)

The calcineurin inhibitor cyclosporine A (CsA) modulates leukocyte cytokine production but may also effect nonimmune cells, including microvascular endothelial cells, which regulate the inflammatory process through leukocyte recruitment. We hypothesized that CsA would promote a proinflammatory phenotype in human intestinal microvascular endothelial cells (HIMEC), by inhibiting inducible nitric-oxide synthase (iNOS, NOS2)-derived NO, normally an important mechanism in limiting endothelial activation and leukocyte adhesion. Primary cultures of HIMEC were used to assess CsA effects on endothelial activation, leukocyte interaction, and the expression of iNOS as well as cell adhesion molecules. CsA significantly increased leukocyte binding to activated HIMEC, but paradoxically decreased endothelial expression of cell adhesion molecules (E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule-1). In contrast, CsA completely inhibited the expression of iNOS in tumor necrosis factor-alpha/lipopolysaccharide-activated HIMEC. CsA blocked p38 MAPK phosphorylation in activated HIMEC, a key pathway in iNOS expression, but failed to inhibit NFkappaB activation. These studies demonstrate that CsA exerts a proinflammatory effect on HIMEC by blocking iNOS expression. CsA exerts a proinflammatory effect on the microvascular endothelium, and this drug-induced endothelial dysfunction may help explain its lack of efficacy in the long-term treatment of chronically active inflammatory bowel disease.
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PMID:Cyclosporine A enhances leukocyte binding by human intestinal microvascular endothelial cells through inhibition of p38 MAPK and iNOS. Paradoxical proinflammatory effect on the microvascular endothelium. 1211 Jun 86

Cytokine-dependent induction of E-selectin expression is mediated through cooperative signaling involving the Ras/Raf/mitogen-activated protein kinase pathway. We previously reported that metastatic tumor cells entering the hepaticcirculation rapidly induce a cytokine cascade leading to E-selectin induction (A-M. Khatib, et al., Cancer Res., 59:1356-1361, 1999).Here, we investigated the effect of a blockade of E-selectin induction on colorectal carcinoma metastasis using rodent (host)-specific C-raf antisense oligonucleotides and human colorectal carcinoma CX-1 cells. Pretreatment of hepatic endothelial cells in vitro with the antisense oligonucleotides abrogated E-selectin-dependent CX-1 adhesion. In vivo, pretreatment of nude mice with these oligonucleotides abrogated E-selectin induction in response to intrasplenic/portal inoculation of CX-1 cells, and this reduced the number of liver metastases by 86% relative to controls. The results suggest that the inhibition of tumor-induced, hepatic microvessel E-selectin expression may provide a useful strategy for the prevention of hepatic metastasis.
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PMID:Inhibition of hepatic endothelial E-selectin expression by C-raf antisense oligonucleotides blocks colorectal carcinoma liver metastasis. 1235 42

Thrombin-stimulated endothelium synthesizes numerous adhesion molecules to recruit leukocytes; however, it is unknown which intracellular pathways are responsible for this event. A recent report from our laboratory has shown that thrombin induces E-selectin expression and that blocking nuclear factor-kappa B (NF-kappa B) activity partially blocked both E-selectin expression (60%) and leukocyte recruitment. In this study, we systematically assessed the importance of p38 MAPK in thrombin-induced NF-kappa B activation and E-selectin-dependent leukocyte recruitment. Thrombin caused phosphorylation of p38 MAPK, its substrate ATF-2, and JNK MAPK, but not ERK MAPK. The p38 MAPK inhibitors, SKF86002 and SB-203580 only reduced ATF-2 activity. We treated human umbilical vein endothelial cells with SKF86002, 1 h before thrombin stimulation, and noted inhibition of NF-kappa B mobilization and complete inhibition of leukocyte rolling and adhesion in a laminar flow chamber. Significant inhibition of leukocyte recruitment and E-selectin expression was also observed with SB-203580. SKF86002 did not affect other systems, including tumor necrosis factor-alpha-induced E-selectin-dependent leukocyte recruitment. Moreover, thrombin-induced rapid mobilization of P-selectin from Weibel Palade bodies was not p38 MAPK dependent. These data suggest that thrombin induces p38 MAPK activation, which leads to NF-kappa B mobilization to the nucleus and causes the upregulation of E-selectin and subsequent leukocyte recruitment.
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PMID:P38 MAPK: critical molecule in thrombin-induced NF-kappa B-dependent leukocyte recruitment. 1250 71

Angiogenesis plays an important role in a variety of pathophysiologic processes, including tumor growth and rheumatoid arthritis. We have previously shown that soluble E-selectin (sE-selectin) is an important angiogenic mediator. However, the mechanism by which sE-selectin mediates angiogenesis is still unknown. In this study, we show that sE-selectin is a potent mediator of human dermal microvascular endothelial cell (HMVEC) chemotaxis, which is predominantly mediated through the Src and the phosphatidylinositiol 3-kinase (PI3K) pathways. Further, sE-selectin induced a 2.2-fold increase in HMVEC tube formation in the Matrigel in vitro assay. HMVECs pretreated with the Src inhibitor (PP2) and the PI3K inhibitor (LY294002) or transfected with Src antisense oligonucleotides or Akt dominant-negative mutants significantly inhibited sE-selectin-mediated HMVEC tube formation. In contrast, HMVECs transfected with an extracellular signal-related kinase 1/2 (ERK1/2) mutant or pretreated with the mitogen-activated protein kinase (MAPK) inhibitor PD98059 failed to show sE-selectin-mediated HMVEC tube formation. Similarly, in the Matrigel-plug in vivo assay, sE-selectin induced a 2.2-fold increase in blood vessel formation, which was significantly inhibited by PP2 and LY294002 but not by PD98059. sE-selectin induced a marked increase in Src, ERK1/2, and PI3K phosphorylation. PI3K and ERK1/2 phosphorylation was significantly inhibited by PP2, thereby suggesting that both of these pathways may be activated via Src kinase. Even though the ERK1/2 pathway was activated by sE-selectin in HMVECs, it seems not to be essential for sE-selectin-mediated angiogenesis. Taken together, our data clearly show that sE-selectin-induced angiogenesis is predominantly mediated through the Src-PI3K pathway.
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PMID:Src and phosphatidylinositol 3-kinase mediate soluble E-selectin-induced angiogenesis. 1252 14

P38 mitogen-activated protein kinase (MAPK) is an important component of intracellular signaling cascades that initiate various inflammatory cellular responses. To determine the role of p38 MAPK in the procoagulant response to lipopolysaccharide (LPS), 24 healthy subjects were exposed to an intravenous dose of LPS (4 ng/kg), preceded 3 hours earlier by orally administered 600 or 50 mg BIRB 796 BS (a specific p38 MAPK inhibitor), or placebo. The 600-mg dose of BIRB 796 BS strongly inhibited LPS-induced coagulation activation, as measured by plasma concentrations of the prothrombin fragment F1 + 2. BIRB 796 BS also dose dependently attenuated the activation and subsequent inhibition of the fibrinolytic system (plasma tissue-type plasminogen activator, plasmin-alpha2-antiplasmin complexes, and plasminogen activator inhibitor type 1) and endothelial cell activation (plasma soluble E-selectin and von Willebrand factor). Activation of p38 MAPK plays an important role in the procoagulant and endothelial cell response after in vivo exposure to LPS.
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PMID:Inhibition of coagulation, fibrinolysis, and endothelial cell activation by a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. 1257 15

Increased levels of isoprostanes have been detected in human atherosclerotic lesions. To examine a possible role for 8-iso-prostaglandin E(2) (8-iso-PGE(2)) in atherogenesis, we tested the effect of 8-iso-PGE(2) on adhesion of leukocytes to human umbilical vein endothelial cells (EC). We demonstrate that 8-iso-PGE(2) stimulates EC to bind monocytes, but not neutrophils. This effect was inhibited by the thromboxane A(2) receptor antagonist SQ29548. Moreover, 8-iso-PGE(2) increased levels of cyclic AMP in EC, and monocyte adhesion induced by 8-iso-PGE(2) was blocked by a protein kinase A inhibitor, H89. In addition, 8-iso-PGE(2 )induced phosphorylation of p38 and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein (MAP) kinase and stimulated expression of EGR-1. A specific inhibitor of p38 MAP kinase (SB203580) abrogated monocyte binding, whereas an inhibitor of the ERK pathway (PD98059) did not block monocyte adhesion induced by 8-iso-PGE(2). Activation of nuclear factor-kappaB (NF-kappaB) and expression of NFkappaB-dependent genes intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin were not induced by 8-iso-PGE(2). Taken together, these results demonstrate that 8-iso-PGE(2) stimulates EC to specifically bind monocytes, but not neutrophils. This effect is mediated by cyclic AMP/protein kinase A- and p38 MAP kinase-dependent pathways and is independent of the classical inflammatory NFkappaB pathway. Thus, formation of 8-iso-PGE(2) may play an important role in chronic inflammatory diseases such as atherosclerosis by increasing adhesion and extravasation of monocytes.
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PMID:The isoprostane 8-iso-PGE2 stimulates endothelial cells to bind monocytes via cyclic AMP- and p38 MAP kinase-dependent signaling pathways. 1271 76

Induction of the alpha1,3-fucosyltransferase FucT-VII in T lymphocytes is crucial for selectin ligand formation, but the signaling and transcriptional pathways that govern FucT-VII expression are unknown. Here, using a novel, highly phorbol myristate acetate (PMA)-responsive variant of the Jurkat T-cell line, we identify Ras and downstream mitogen-activated protein (MAP) kinase pathways as essential mediators of FucT-VII gene expression. PMA induced FucT-VII in only a subset of treated cells, similar to expression of FucT-VII in normal activated CD4 T cells. Introduction of constitutively active Ras or Raf by recombinant retroviruses induced FucT-VII expression only in that subset of cells expressing the highest levels of Ras, suggesting that induction of FucT-VII required a critical threshhold of Ras signaling. Both PMA treatment and introduction of active Ras led to rolling on E-selectin. Pharmacologic inhibition studies confirmed the involvement of the classic Ras-Raf-MEK-extracellular signal-regulated kinase (Ras-Raf-MEK-ERK) pathway in FucT-VII induction by PMA, Ras, and Raf. These studies also revealed a second, Ras-induced, Raf-1-independent pathway that participated in induction of FucT-VII. Strong activation of Ras represents a major pathway for induction of FucT-VII gene expression in T cells.
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PMID:Induction of FucT-VII by the Ras/MAP kinase cascade in Jurkat T cells. 1273 75

The interaction of circulating leukocytes with lung microvessels is a critical event in the recruitment of effector cells into the interstitial tissue during episodes of inflammation, including smoking-induced chronic airway disease. In the present study, murine lung tissue transplanted into a dorsal skinfold window chamber in nude mice was used as a model system to study nicotine-induced leukocyte trafficking in vivo. The revascularized lung microvessels were determined to be of pulmonary origin based on their ability to constrict in response to hypoxia. We demonstrated that nicotine significantly enhanced rolling and adhesion of leukocytes within lung microvessels comprising arterioles and postcapillary venules in a dose-dependent manner, but failed to induce leukocyte emigration. Nicotine-induced rolling and adhesion was significantly higher in venules than in arterioles. Treatment of mice with monoclonal antibodies (MAbs) against L-, E-, or P-selectin after exposure of lung allografts to nicotine resulted in variable but significant inhibition of nicotine-induced rolling, whereas nicotine-induced subsequent adhesion was inhibited by MAbs against L- and P-selectin but not E-selectin. Exposure of lung allografts to nicotine along with PD-98059, a mitogen-activated protein kinase (MAPK)-specific inhibitor, resulted in significant inhibition of nicotine-induced rolling and adhesion. In vitro, exposure of murine lung endothelial cells to nicotine resulted in increased phosphorylation of mitogen-activated/extracellular signal-regulated protein kinase 1/2, which could be blocked by PD-98059. Overall, these results suggest that nicotine-induced inflammation in the airways could potentially be due to MAPK-mediated, selectin-dependent leukocyte-endothelial cell interactions in the lung microcirculation.
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PMID:Selectin-dependent rolling and adhesion of leukocytes in nicotine-exposed microvessels of lung allografts. 1279 8

Lipopolysaccharide (endotoxin) tolerance is well described in monocytes and macrophages, but is less well characterized in endothelial cells. Because intestinal microvascular endothelial cells exhibit a strong immune response to LPS challenge and play a critical regulatory role in gut inflammation, we sought to characterize the activation response of these cells to repeated LPS exposure. Primary cultures of human intestinal microvascular endothelial cells (HIMEC) were stimulated with LPS over 6-60 h and activation was assessed using U937 leukocyte adhesion, expression of E-selectin, ICAM-1, VCAM-1, IL-6, IL-8, manganese superoxide dismutase, HLA-DR, and CD86. Effect of repeat LPS stimulation on HIMEC NF-kappaB and mitogen-activated protein kinase (MAPK) activation, generation of superoxide anion, and Toll-like receptor 4 expression was characterized. LPS pretreatment of HIMEC for 24-48 h significantly decreased leukocyte adhesion after subsequent LPS stimulation. LPS pretreatment inhibited expression of E-selectin, VCAM-1, IL-6, and CD86, while ICAM-1, IL-8, and HLA-DR were not altered. Manganese superoxide dismutase expression increased with repeated LPS stimulation, with a reduction in intracellular superoxide. NF-kappaB activation was transiently inhibited by LPS pretreatment for 6 h, but not at later time points. In contrast, p44/42 MAPK, p38 MAPK, and c-Jun N-terminal kinase activation demonstrated inhibition by LPS pretreatment 24 or 48 h prior. Toll-like receptor 4 expression on HIMEC was not altered by LPS. HIMEC exhibit endotoxin tolerance after repeat LPS exposure in vitro, characterized by diminished activation and intracellular superoxide anion concentration, and reduced leukocyte adhesion. HIMEC possess specific mechanisms of immunoregulatory hyporesponsiveness to repeated LPS exposure.
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PMID:Mechanisms of endotoxin tolerance in human intestinal microvascular endothelial cells. 1279 22

Gastroesophageal reflux disease is the most common malady of the esophagus, affecting 7% of the United States population. Histological assessment demonstrates classic inflammatory mechanisms including selective leukocyte recruitment and hemorrhage, suggesting a prominent role for the microvasculature. We isolated and characterized human esophageal microvascular endothelial cells (EC) (HEMEC), examined inflammatory activation in response to cytokines, LPS, and acidic pH exposure, and identified signaling pathways that underlie activation. HEMEC displayed characteristic morphological and phenotypic features including acetylated LDL uptake. TNF-alpha/LPS activation of HEMEC resulted in upregulation of the cell adhesion molecules (CAM) ICAM-1, VCAM-1, E-selectin, and mucosal addressin CAM-1 (MAdCAM-1), increased IL-8 production, and enhanced leukocyte binding. Both acid and TNF-alpha/LPS activation lead to activation of SAPK/JNK in HEMEC that was linked to VCAM-1 expression and U-937 leukocyte adhesion. Expression of constitutive inducible nitric oxide synthase in HEMEC was in marked contrast to intestinal microvascular endothelial cells. In this study, we demonstrate that HEMECs are phenotypically and functionally distinct from lower gut-derived endothelial cells and will facilitate understanding of inflammatory mechanisms in esophageal inflammation.
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PMID:Isolation and characterization of human esophageal microvascular endothelial cells: mechanisms of inflammatory activation. 1291 42


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