Copyright © 2005, European Society of Cardiology
Role of the JNK pathway in thrombin-induced ICAM-1 expression in endothelial cells
aDepartment of Medicine and Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
bCardiovascular Physiology and Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Japan
cDepartment of Human Genetics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan
dClinical Laboratory Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Japan
* Corresponding author. Tel.: +81 82 257 5122; fax: +81 82 257 5124. Email address: ishidat{at}hiroshima-u.ac.jp
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-
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% and 72 ± 7%, respectively). In contrast, inhibitors of MEK and p38 had only minimal effect. The combination of SP600125 and the NF-B inhibitor, BAY11-7082, resulted in complete inhibition of thrombin-induced ICAM-1 expression. The G
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 βARK1ct (a Gβ
subunit scavenger) and Csk.
Conclusions: These data suggest that, in concert with NF-B, JNK regulates thrombin-induced ICAM-1 expression by a mechanism that is dependent on Gq, Gβ, Ras, Rac1 and the Src kinase family.
KEYWORDS G proteins; Gene expression; MAP kinase; Signal transduction
Time for primary review 26 days
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