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Molecular and Cellular Biology, August 2001, p. 5554-5565, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5554-5565.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Protein Kinase C-delta Regulates Thrombin-Induced ICAM-1 Gene Expression in Endothelial Cells via Activation of p38 Mitogen-Activated Protein Kinase

Arshad Rahman,1,* Khandaker N. Anwar,1 Shahab Uddin,2,3 Ning Xu,1 Richard D. Ye,1 Leonidas C. Platanias,2,3 and Asrar B. Malik1

Department of Pharmacology1 and Section of Hematology-Oncology,2 The University of Illinois College of Medicine, Chicago, Illinois 60612, and West Side Veteran Affairs Hospital, Chicago, Illinois 606073

Received 30 October 2000/Returned for modification 16 January 2001/Accepted 25 May 2001

The procoagulant thrombin promotes the adhesion of polymorphonuclear leukocytes to endothelial cells by a mechanism involving expression of intercellular adhesion molecule 1 (ICAM-1) via an NF-kappa B-dependent pathway. We now provide evidence that protein kinase C-delta (PKC-delta ) and the p38 mitogen-activated protein (MAP) kinase pathway play a critical role in the mechanism of thrombin-induced ICAM-1 gene expression in endothelial cells. We observed the phosphorylation of PKC-delta and p38 MAP kinase within 1 min after thrombin challenge of human umbilical vein endothelial cells. Pretreatment of these cells with the PKC-delta inhibitor rottlerin prevented the thrombin-induced phosphorylation of p38 MAP kinase, suggesting that p38 MAP kinase signals downstream of PKC-delta . Inhibition of PKC-delta or p38 MAP kinase by pharmacological and genetic approaches markedly decreased the thrombin-induced NF-kappa B activity and resultant ICAM-1 expression. The effects of PKC-delta inhibition were secondary to inhibition of IKKbeta activation and of subsequent NF-kappa B binding to the ICAM-1 promoter. The effects of p38 MAP kinase inhibition occurred downstream of Ikappa Balpha degradation without affecting the DNA binding function of nuclear NF-kappa B. Thus, PKC-delta signals thrombin-induced ICAM-1 gene transcription by a dual mechanism involving activation of IKKbeta , which mediates NF-kappa B binding to the ICAM-1 promoter, and p38 MAP kinase, which enhances transactivation potential of the bound NF-kappa B p65 (RelA).


* Corresponding author. Mailing address: Department of Pharmacology (M/C 868), University of Illinois College of Medicine, 835 South Wolcott Ave., Chicago, IL 60612-7343. Phone: (312) 355-0242. Fax: (312) 413-0222. E-mail: ARahman{at}uic.edu.


Molecular and Cellular Biology, August 2001, p. 5554-5565, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5554-5565.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.



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