Role of the JNK pathway in thrombin-induced ICAM-1 expression in endothelial cells
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Objective: Thrombin induces leukocyte adherence to endothelial cells via increased expression of intercellular adhesion molecule-1 (ICAM-1). Although ICAM-1 expression is regulated by NF-kappa B, recent studies have suggested that additional signaling mechanisms may also be involved. The goal of this study was to determine whether mitogen-activated protein (MAP) kinases, including extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 MAP kinase (p38), mediate thrombin-induced ICAM-1 expression in endothelial cells.Methods: Western blot analysis using anti-ICAM-1 antibody and luciferase assays were performed in cultured endothelial cells after addition of signal transduction inhibitors or transfection of various gene constructs. JNK kinase activity was determined by a kinase assay using c-Jun as a substrate or by Western blot analysis with anti-phospho-JNK antibody.Results: Treatment of endothelial cells with the JNK-specific inhibitors, SP600125 or JNK inhibitory peptide 1 (JNKI1), resulted in a significant decrease in thrombin-induced ICAM-1 expression as demonstrated by Western blot analysis (67 +/- 3 0x1.535a8bfffb01p-890nd 72 +/- 7%, respectively). In contrast, inhibitors of MEK and p38 had only minimal effect. The combination of SP600125 and the NF-kappa B inhibitor, BAY 11-7082, resulted in complete inhibition of thrombin-induced ICAM-1 expression. The G(alpha q) inhibitor, YM-254890, inhibited thrombin-induced JNK activation and ICAM-1 expression. Dominant-negative Ras and Rac1, but not Rho, inhibited thrombin-induced JNK activation and ICAM-1 promoter activity. Finally, thrombin-induced JNK activation and ICAM-1 promoter activity were inhibited by beta ARK1ct (a G beta gamma subunit scavenger) and Csk.Conclusions: These data suggest that, in concert with NF-kappa B, JNK regulates thrombin-induced ICAM-1 expression by a mechanism that is dependent on G(alpha q), G beta gamma, Ras, Rac1 and the Src kinase family.
- 2005-11-01
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