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J. Biol. Chem., Vol. 283, Issue 7, 4210-4218, February 15, 2008

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Role of NF-B-dependent Caveolin-1 Expression in the Mechanism of Increased Endothelial Permeability Induced by Lipopolysaccharide^*

From the Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois 60612

We investigated the role of NF-B activation by the bacterial product lipopolysaccharide (LPS) in inducing caveolin-1 (Cav-1) expression and its consequence in contributing to the leakiness of the endothelial barrier. We observed that LPS challenge of human lung microvascular endothelial cells induced concentration- and time-dependent increases in expression of Cav-1 mRNA and protein. The NEMO (NF-B essential modifier binding domain)-binding domain peptide (IkB kinase (IKK)-NEMO-binding domain (NBD) peptide), which prevents NF-B activation by inhibiting the interaction of IKK with the IKK complex, blocked LPS-induced Cav-1 mRNA and protein expression. Knockdown of NF-B subunit p65/RelA expression with small interfering RNA also prevented LPS-induced Cav-1 expression. Caveolae open to the apical and basal plasmalemma of endothelial cells increased 2-4-fold within 4 h of LPS exposure. IKK-NBD peptide markedly reduced the LPS-induced increase in the number of caveolae as well as transendothelial albumin permeability. These observations were recapitulated in mouse studies in which IKK-NBD peptide prevented Cav-1 expression and interfered with the increase in lung microvessel permeability induced by LPS. Thus, LPS mediates NF-B-dependent Cav-1 expression that results in increased caveolae number and thereby contributes to the mechanism of increased transendothelial albumin permeability.

Received for publication, April 13, 2007 , and in revised form, November 19, 2007.

^* This study was supported by National Institutes of Health Grants P01HL060678, P01HL077806, R01GM58531, and R01HL045638. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pharmacology (M/C 868), University of Illinois, 835 South Wolcott Ave., Chicago, IL 60612. Tel.: 312-996-7635; Fax: 312-996-1225; E-mail: abmalik{at}uic.edu.

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