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J. Biol. Chem., Vol. 282, Issue 47, 33958-33967, November 23, 2007

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Endotoxin Priming of Neutrophils Requires NADPH Oxidase-generated Oxidants and Is Regulated by the Anion Transporter ClC-3^*

Jessica G. Moreland¹, A. Paige Davis, James J. Matsuda, Jessica S. Hook, Gail Bailey, William M. Nauseef^¶, and Fred S. Lamb

From the Division of Critical Care, Department of Pediatrics, The Inflammation Program, and ^¶Department of Internal Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa 52242

Several soluble mediators, including endotoxin, prime neutrophils for an enhanced respiratory burst in response to subsequent stimulation. Priming of neutrophils occurs in vitro, and primed neutrophils are found in vivo. We previously localized the anion transporter ClC-3 to polymorphonuclear leukocytes (PMN) secretory vesicles and demonstrated that it is required for normal NADPH oxidase activation in response to both particulate and soluble stimuli. We now explore the contribution of the NADPH oxidase and ClC-3 to endotoxin-mediated priming. Lipooligosaccharide (LOS) from Neisseria meningitidis enhances the respiratory burst in response to formyl-Met-Leu-Phe, an effect that was impaired in PMNs lacking functional ClC-3 and under anaerobic conditions. Mobilization of receptors to the cell surface and phosphorylation of p38 MAPK by LOS were both impaired in PMN with the NADPH oxidase chemically inhibited or genetically absent and in cells lacking functional ClC-3. Furthermore, inhibition of the NADPH oxidase or ClC-3 in otherwise unstimulated cells elicited a phenotype similar to that seen after endotoxin priming, suggesting that basal oxidant production helps to maintain cellular quiescence. In summary, NADPH oxidase activation was required for LOS-mediated priming, but basal oxidants kept unstimulated cells from becoming primed. ClC-3 contributes to both of these processes.

Received for publication, June 27, 2007 , and in revised form, September 27, 2007.

^* The work was supported by the Grants AI067533 (to J. G. M.), HL62483-06 (to F. S. L.), AI 34879-19 (to W. M. N.), P01 AI4462 (to J. G. M. and W. M. N.), 5K12 HD047349 (to A. P. D.), and DK07690-15 (to J. J. M.). 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: Division of Pediatric Critical Care, Dept. of Pediatrics, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242. Tel.: 319-356-1615; Fax: 319-353-8597; E-mail: jessica-moreland{at}uiowa.edu.

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