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J. Biol. Chem., Vol. 282, Issue 9, 6116-6125, March 2, 2007

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Blockade of Class IA Phosphoinositide 3-Kinase in Neutrophils Prevents NADPH Oxidase Activation- and Adhesion-dependent Inflammation^*

Xiao-Pei Gao¹, Xiangdong Zhu¹, Jian Fu, Qinghui Liu, Randall S. Frey, and Asrar B. Malik²

From the Department of Pharmacology and Center of Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois 60612 and the Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago, Chicago, Illinois 60637

We examined the role of class IA phosphoinositide 3-kinase (PI3K) in the regulation of activation of NADPH oxidase in PMNs and the mechanism of PMN-dependent lung inflammation and microvessel injury induced by the pro-inflammatory cytokine TNF-. TNF- stimulation of PMNs resulted in superoxide production that was dependent on CD11b/CD18-mediated PMN adhesion. Additionally, TNF- induced the association of CD11b/CD18 with the NADPH oxidase subunit Nox2 (gp91^phox) and phosphorylation of p47^phox, indicating the CD11b/CD18 dependence of NADPH oxidase activation. Transduction of wild-type PMNs with p85 protein, a dominant-negative form of the class IA PI3K regulatory subunit, p85, fused to HIV-TAT (TAT-p85) prevented (i) CD11b/CD18-dependent PMN adhesion, (ii) interaction of CD11b/CD18 with Nox2 and phosphorylation of p47^phox, and (iii) PMN oxidant production. Furthermore, studies in mice showed that i.v. infusion of TAT-p85 significantly reduced the recruitment of PMNs in lungs and increase in lung microvascular permeability induced by TNF-. We conclude that class IA PI3K serves as a nodal point regulating CD11b/CD18-integrin-dependent PMN adhesion and activation of NADPH oxidase, and leads to oxidant production at sites of PMN adhesion, and the resultant lung microvascular injury in mice.

Received for publication, November 2, 2006 , and in revised form, December 14, 2006.

^* This study was supported in part by National Institutes of Health Grants HL46350, HL77806, HL45638, and HL64573 (to A. B. M.), and AI52109 (to X. Z.) and by 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pharmacology, College of Medicine, The University of Illinois, 835 South Wolcott Ave., Chicago, IL 60612-7343. Tel.: 312-996-7635; Fax: 312-996-1225; E-mail: abmalik{at}uic.edu.

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