Protein kinase C-delta regulates thrombin-induced ICAM-1 gene expression in endothelial cells via activation of p38 mitogen-activated protein kinase

The procoagulant thrombin promotes the adhesion of polymorphonuclear leukoc ytes to endothelial cells by a mechanism involving expression of intercellu lar adhesion molecule 1 (ICAM- 1) via an NF-kappaB-dependent pathway. We no w provide evidence that protein kinase C-delta (PKC-delta) and the p38 mito gen-activated protein (MAP) kinase pathway play a critical role in the mech anism of thrombin-induced ICAM-1 gene expression in endothelial cells. We o bserved the phosphorylation of PKC-delta and p38 MAP kinase within 1 min af ter thrombin challenge of human umbilical vein endothelial cells. Pretreatm ent of these cells with the PKC-delta inhibitor rottlerin prevented the thr ombin-induced phosphorylation of p38 MAP kinase, suggesting that p38 MAP ki nase signals downstream of PKC-delta. Inhibition of PKC-delta or p38 MAP ki nase by pharmacological and genetic approaches markedly decreased the throm bin-induced NF-kappaB activity and resultant ICAM-1 expression. The effects of PKC-delta inhibition were secondary to inhibition of IKK beta activatio n and of subsequent NF-kappaB binding to the ICAM-1 promoter. The effects o f p38 MAP kinase inhibition occurred downstream of I kappaB alpha degradati on without affecting the DNA binding function of nuclear NF-kappaB. Thus, P KC-delta signals thrombin-induced ICAM-1 gene transcription by a dual mecha nism involving activation of IKK beta, which mediates NF-kappaB binding to the ICAM-1 promoter, and p38 MAP kinase, which enhances transactivation pot ential of the bound NF-kappaB p65 (RelA).