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J. Biol. Chem., Vol. 279, Issue 52, 54023-54031, December 24, 2004

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The Function of Mitogen-activated Protein Kinase Phosphatase-1 in Peptidoglycan-stimulated Macrophages^*

Edward G. Shepherd, Qun Zhao, Stephen E. Welty, Thomas N. Hansen, Charles V. Smith, and Yusen Liu

From the Center for Developmental Pharmacology and Toxicology, Children's Research Institute, Children's Hospital, the Department of Pediatrics, Ohio State University, Columbus, Ohio 43205

Mitogen-activated protein (MAP) kinases play a pivotal role in the macrophages in the production of proinflammatory cytokines triggered by lipopolysaccharides. However, their function in the responses of macrophages to Gram-positive bacteria is poorly understood. Even less is known about the attenuation of MAP kinase signaling in macrophages exposed to Gram-positive bacteria. In the present study, we have investigated the regulation of MAP kinases and the role of MAP kinase phosphatase (MKP)-1 in the production of pro-inflammatory cytokines using murine RAW264.7 and primary peritoneal macrophages after peptidoglycan stimulation. Treatment of macrophages with peptidoglycan resulted in a transient activation of JNK, p38, and extracellular signal-regulated kinase. Most interestingly, MKP-1 expression was potently induced by peptidoglycan, and this induction was concurrent with MAP kinase dephosphorylation. Triptolide, a diterpenoid triepoxide, potently blocked the induction of MKP-1 by peptidoglycan and prolonged the activation of JNK and p38. Overexpression of MKP-1 substantially attenuated the production of tumor necrosis factor (TNF)- induced by peptidoglycan, whereas knockdown of MKP-1 by small interfering RNA substantially increased the production of both TNF- and interleukin-1. Finally, we found that in primary murine peritoneal macrophages, MKP-1 induction following peptidoglycan stimulation also coincided with inactivation of JNK and p38. Blockade of MKP-1 induction resulted in a sustained activation of both JNK and p38 in primary macrophages. Our results reveal that MKP-1 critically regulates the expression of TNF- and interleukin-1 in RAW264.7 cells and further suggest a central role for this phosphatase in controlling the inflammatory responses of primary macrophages to Gram-positive bacterial infection.

Received for publication, July 26, 2004 , and in revised form, October 4, 2004.

^* This work was supported by NIAID Grant AI57798 (to Y. L.) and NICHD Grant HD43003 (to T. N. H.) 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, Ohio State University, 700 Children's Dr., Columbus, OH 43205. Tel.: 614-722-3703; Fax: 614-722-3455; E-mail: liuy{at}pediatrics.ohio-state.edu.

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