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B Kinase 
and Phosphorylation of RelA/p651
* Department of Pediatrics, University of Rochester School of Medicine, Rochester, NY 14642; and
Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612
We investigated the involvement of the RhoA/Rho-associated kinase (ROCK) pathway in regulating ICAM-1 expression in endothelial cells by the procoagulant, thrombin. Exposure of HUVECs to C3 exoenzyme, a selective inhibitor of Rho, markedly reduced thrombin-induced ICAM-1 expression. Inhibition of ROCK, the downstream effector of Rho, also prevented thrombin-induced ICAM-1 expression. Blockade of thrombin-induced ICAM-1 expression was secondary to inhibition of NF-
B activity, the key regulator of ICAM-1 expression in endothelial cells. In parallel studies we observed that inhibition of the RhoA/ROCK pathway by the same pharmacological and genetic approaches failed to inhibit TNF-
-induced NF-B activation and ICAM-1 expression. The effect of RhoA/ROCK inhibition on thrombin-induced NF-B activation was secondary to inhibition of IB kinase activation and subsequent IB degradation and nuclear uptake and the DNA binding of NF-B. Inhibition of the RhoA/ROCK pathway also prevented phosphorylation of Ser536 within the transactivation domain 1 of NF-B p65/RelA, a critical event conferring transcriptional competency to the bound NF-B. Thus, the RhoA/ROCK pathway signals thrombin-induced ICAM-1 expression through the activation of IB kinase, which promotes NF-B binding to ICAM-1 promoter and phosphorylation of RelA/p65, thus mediating the transcriptional activation of bound NF-B.
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