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J. Biol. Chem., Vol. 281, Issue 23, 16128-16138, June 9, 2006

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Phosphatidylinositol 3-Kinase Signaling through Protein Kinase C Induces NADPH Oxidase-mediated Oxidant Generation and NF-B Activation in Endothelial Cells^*

Randall S. Frey¹, Xiaopei Gao, Kamran Javaid, Shahid S. Siddiqui, Arshad Rahman, and Asrar B. Malik

From the Department of Pharmacology and Center for Lung and Vascular Biology, the University of Illinois College of Medicine, Chicago, Illinois 60612 and the Departments of Pediatrics and Environmental Medicine, University of Rochester School of Medicine, Rochester, New York 14642

We addressed the role of class 1B phosphatidylinositol 3-kinase (PI3K) isoform PI3K in mediating NADPH oxidase activation and reactive oxidant species (ROS) generation in endothelial cells (ECs) and of PI3K-mediated oxidant signaling in the mechanism of NF-B activation and intercellular adhesion molecule (ICAM)-1 expression. We used lung microvascular ECs isolated from mice with targeted deletion of the p110 catalytic subunit of PI3K. Tumor necrosis factor (TNF) challenge of wild type ECs caused p110 translocation to the plasma membrane and phosphatidylinositol 1,4,5-trisphosphate production coupled to ROS production; however, this response was blocked in p110^–/– ECs. ROS production was the result of TNF activation of Ser phosphorylation of NADPH oxidase subunit p47^phox and its translocation to EC membranes. NADPH oxidase activation failed to occur in p110^–/– ECs. Additionally, the TNF-activated NF-B binding to the ICAM-1 promoter, ICAM-1 protein expression, and PMN adhesion to ECs required functional PI3K. TNF challenge of p110^–/– ECs failed to induce phosphorylation of PDK1 and activation of the atypical PKC isoform, PKC. Thus, PI3K lies upstream of PKC in the endothelium, and its activation is crucial in signaling NADPH oxidase-dependent oxidant production and subsequent NF-B activation and ICAM-1 expression.

Received for publication, August 10, 2005 , and in revised form, February 21, 2006.

^* This work was supported in part by National Institutes of Health Grants T32 HL07239 and HL60678 (to A. B. M.) and HL67424 (to A. R.) and a research grant from the American Lung Association (to R. S. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, University of Illinois College of Medicine, 835 S. Wolcott Ave., E403, Chicago, IL 60612. Tel.: 312-413-3428; Fax: 312-996-1225; E-mail. RFrey{at}uic.edu.

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