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J. Biol. Chem., Vol. 279, Issue 20, 20889-20897, May 14, 2004

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Peptidoglycan Induces Nuclear Factor-B Activation and Cyclooxygenase-2 Expression via Ras, Raf-1, and ERK in RAW 264.7 Macrophages^*

Bing-Chang Chen, Ya-Sheng Chang, Ju-Chiun Kang¶, Ming-Jen Hsu, Joen-Rong Sheu¶, Ta-Liang Chen||, Che-Ming Teng**, and Chien-Huang Lin

From the School of Respiratory Therapy, Graduate Institute of Biomedical Technology, the ^¶Department of Pharmacology, School of Medicine, Taipei Medical University, the ^||Department of Anesthesiology, Taipei Medical University-Wan Fang Hospital, and ^**Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 110, Taiwan

In this study, we investigated the signaling pathway involved in cyclooxygenase-2 (COX-2) expression caused by peptidoglycan (PGN), a cell wall component of the Gram-positive bacterium Staphylococcus aureus, in RAW 264.7 macrophages. PGN caused dose- and time-dependent increases in COX-2 expression, which was attenuated by a Ras inhibitor (manumycin A), a Raf-1 inhibitor (GW 5074), and an MEK inhibitor (PD 098059). Treatment of RAW 264.7 macrophages with PGN caused time-dependent activations of Ras, Raf-1, and ERK. The PGN-induced increase in Ras activity was inhibited by manumycin A. Raf-1 phosphorylation at Ser-338 by PGN was inhibited by manumycin A and GW 5074. The PGN-induced increase in ERK activity was inhibited by manumycin A, GW 5074, and PD 098059. Stimulation of cells with PGN activated IB kinase / (IKK/), IB phosphorylation, IB degradation, and B-luciferase activity. Treatment of macrophages with an NF-B inhibitor (pyrrolidine dithiocarbamate), an IB phosphorylation inhibitor (Bay 117082), and IB protease inhibitors (L-1-tosylamido-2-phenylethyl chloromethyl ketone and calpain inhibitor I) all inhibited PGN-induced COX-2 expression. The PGN-mediated increase in the activities of IKK/ and B-luciferase were also inhibited by the Ras dominant negative mutant (RasN17), manumycin A, GW 5074, and PD 098059. Further studies revealed that PGN induced the recruitment of p85 and Ras to Toll-like receptor 2 in a time-dependent manner. Our data demonstrate for the first time that PGN activates the Ras/Raf-1/ERK pathway, which in turn initiates IKK/ and NF-B activation, and ultimately induces COX-2 expression in RAW 264.7 macrophages.

Received for publication, October 14, 2003 , and in revised form, March 4, 2004.

^* This work was supported by Grant NSC 92-2314-B-038-059 from the National Science Council of Taiwan. 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: School of Respiratory Therapy, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. Tel.: 886-2-27361661 (ext. 3510); Fax: 886-2-27397313; E-mail: chlin{at}tmu.edu.tw.

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