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cAMP targeting of p38 MAP kinase inhibits thrombin-induced NF-B activation and ICAM-1 expression in endothelial cells

¹Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642; and ²Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60612

Submitted 4 March 2004 ; accepted in final form 6 July 2004

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 to forskolin or dibutyryl cAMP, 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-B p65 (RelA) subunit, a crucial event promoting the activation of the DNA-bound NF-B. Because p38 MAPK can induce transcriptional activity of RelA/p65 without altering the DNA binding function of NF-B, we addressed the possibility that cAMP antagonizes thrombin-induced NF-B activity and ICAM-1 expression by preventing the activation of p38 MAPK. We observed that treating cells with forskolin blocked the activation of p38 MAPK, and inhibition of p38 MAPK 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 MAPK activation, which in turn prevents phosphorylation of RelA/p65 and transcriptional activity of the bound NF-B.

endothelial adhesivity; polymorphonuclear leukocytes; IB degradation; RelA/p65 phosphorylation; mitogen-activated protein kinase; nuclear factor-B; intercellular adhesion molecule-1; cyclic adenosine 5'-monophosphate

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