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J. Biol. Chem., Vol. 283, Issue 16, 10822-10834, April 18, 2008

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Actin S-Nitrosylation Inhibits Neutrophil β₂ Integrin Function^*

Stephen R. Thom¹, Veena M. Bhopale, D. Joshua Mancini², and Tatyana N. Milovanova

From the Institute for Environmental Medicine, Department of Emergency Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-6068

The focus of this work was to elucidate the mechanism for inhibition of neutrophil β₂ integrin adhesion molecules by hyperoxia. Results demonstrate that exposure to high oxygen partial pressures increases synthesis of reactive species derived from type 2 nitric-oxide synthase and myeloperoxidase, leading to excessive S-nitrosylation of β-actin and possibly profilin. Hyperoxia causes S-nitrosylation of the four cysteine moieties closest to the carboxyl-terminal end of actin, which results in formation of short actin filaments. This alters actin polymerization, network formation, and intracellular distribution, as well as inhibits β₂ integrin clustering. If neutrophils are exposed to ultraviolet light to reverse S-nitrosylation, or are incubated with N-formyl-methionyl-leucine-phenylalanine to trigger "inside-out" activation, the effects of hyperoxia are reversed. We conclude that cytoskeletal changes triggered by hyperoxia inhibit β₂ integrin-dependent neutrophil adhesion.

Received for publication, November 8, 2007 , and in revised form, January 28, 2008.

^* This work was supported by a grant from the Office of Naval Research. 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. 1-3.

² Present address: Dept. of Surgery, Hitchcock Hospital and Dartmouth University, Hanover, NH 02747.

¹ To whom correspondence should be addressed: Institute for Environmental Medicine, University of Pennsylvania, 1 John Morgan Bldg., 3620 Hamilton Walk, Philadelphia, PA 19104-6068. Tel.: 215-898-9095; Fax: 215-573-7037; E-mail: sthom{at}mail.med.upenn.edu.

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