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J. Biol. Chem., Vol. 280, Issue 9, 8101-8108, March 4, 2005

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The Role of Mitogen-activated Protein Kinase Phosphatase-1 in the Response of Alveolar Macrophages to Lipopolysaccharide

ATTENUATION OF PROINFLAMMATORY CYTOKINE BIOSYNTHESIS VIA FEEDBACK CONTROL OF p38^*

Qun Zhao, Edward G. Shepherd, Mary E. Manson, Leif D. Nelin, Andrey Sorokin, and Yusen Liu¶

From the Center for Developmental Pharmacology and Toxicology, Children's Research Institute, Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus, Ohio 43205 and the Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Mitogen-activated protein (MAP) kinases are critical mediators of innate immune responses. In response to lipopolysaccharide (LPS), MAP kinases are rapidly activated and play an important role in the production of proinflammatory cytokines. Although a number of MAP kinase phosphatases (MKPs) have been identified, their roles in the control of cytokine production have not been well defined. In the present report, we investigated the role of MKP-1 in alveolar macrophages stimulated with LPS. We found that LPS triggered transient activation of three MAP kinase subfamilies, ERK, JNK, and p38, in both immortalized and primary murine alveolar macrophages. MKP-1 was rapidly induced by LPS, and its induction correlated with the dephosphorylation of these MAP kinases. Blocking MKP-1 with triptolide prolonged the activities of both JNK and p38 in immortalized alveolar macrophages. Stimulation of primary alveolar macrophages isolated from MKP-1-deficient mice with LPS resulted in a prolonged p38 phosphorylation compared with wild type alveolar macrophages. Accordingly, these MKP-1-deficient alveolar macrophages also mounted a more robust and rapid tumor necrosis factor production than their wild type counterparts. Adenovirus-mediated MKP-1 overexpression significantly attenuated tumor necrosis factor production in immortalized alveolar macrophages. Finally, MKP-1 was induced by a group of corticosteroids frequently prescribed for the treatment of inflammatory lung diseases, and the anti-inflammatory potencies of these drugs closely correlated with their abilities to induce MKP-1. Our studies indicated that MKP-1 plays an important role in dampening the inflammatory responses of alveolar macrophages. We speculate that MKP-1 may represent a novel target for therapeutic intervention of inflammatory lung diseases.

Received for publication, October 15, 2004

^* This work was supported by Grant R01AI57798 from NIAID of the National Institutes of Health (to Y. L.), Grant R01HL22563 from the NHLBI of the National Institutes of Health (to A. S.), and Training Grant T32HD043003 from the National Institutes of Health. 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.

^¶ To whom correspondence should be addressed: Center for Developmental Pharmacology and Toxicology, Children's Research Institute, Children's Hospital, Dept. of Pediatrics, The Ohio State University, 700 Children's Dr., Columbus, OH 43205. Tel.: 614-722-3073; Fax: 614-355-3455; E-mail: liuy{at}pediatrics.ohio-state.edu.

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