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B Activation and ICAM-1 Expression in Endothelial Cells
1 Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, Afghanistan
2 Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL, USA
* To whom correspondence should be addressed. E-mail: Arshad_Rahman{at}urmc.rochester.edu.
We investigated the mechanisms by which elevated intracellular cAMP concentration inhibits the thrombin-induced ICAM-1 expression in endothelial cells. Exposure of human umbilical vein endothelial cells (HUVEC) to forskolin or dibutyryl cAMP (dbcAMP), which increase intracellular cAMP by separate mechanisms, inhibited the thrombin-induced ICAM-1 expression. This effect of cAMP was secondary to inhibition of NF-
B activity, the key regulator of thrombin-induced ICAM-1 expression in endothelial cells. The action of cAMP occurred downstream of IB
degradation and was independent of NF-B binding to the ICAM-1 promoter. We observed that cAMP interfered with thrombin-induced phosphorylation of NF-
Bp65 (RelA) subunit, a crucial event promoting the activation of the DNA-bound NF-B. As
p38 MAP kinase can induce transcriptional activity of RelA/p65 without altering the DNA binding function of NF-B, we addressed the possibility that cAMP antagonizes thrombininduced NF-B activity and ICAM-1 expression by preventing the activation of p38 MAP kinase. We observed that treating cells with forskolin blocked the activation of p38 MAP kinase and inhibition of p38 MAP kinase interfered with phosphorylation of RelA/p65 induced by thrombin. Our data demonstrate that increased intracellular cAMP concentration in endothelial cells prevents thrombin-induced ICAM-1 expression by inhibiting p38 MAP kinase activation, which in turn prevents phosphorylation of RelA/p65 and transcriptional activity of the bound NF-B.
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