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J. Biol. Chem., Vol. 279, Issue 8, 6629-6634, February 20, 2004

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Involvement of IRAK-M in Peptidoglycan-induced Tolerance in Macrophages^*

Kuniko Nakayama, Shu Okugawa, Shintaro Yanagimoto, Takatoshi Kitazawa, Kunihisa Tsukada, Miki Kawada, Satoshi Kimura, Koichi Hirai, Yohtaroh Takagaki, and Yasuo Ota¶

From the Departments of Infectious Diseases and Bioregulatory Function, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan and the Department of Molecular Medicine, Graduate School of Medicine, Kitasato University, Sagamihara, Kanagawa 228-8555, Japan

The molecular mechanisms by which pathogen-associated molecular patterns recognized by TLR2, such as peptidoglycan (PGN), induce homotolerance are largely unknown. It was recently reported that IRAK-M negatively regulates TLR signaling. In this study, we elucidate the molecular mechanisms of tolerance induced by PGN, with a focus on the role of IRAK-M. We demonstrate that pretreatment of macrophage RAW264.7 cells with a high concentration (30 µg/ml) of PGN for 16 h effectively induces tolerance against following stimulation with 30 µg/ml of PGN; while pretreatment with a low concentration (1 µg/ml) of PGN does not. IRAK-M is induced in cells treated with the high concentration of PGN 4–24 h after PGN stimulation, but not in cells treated with the low concentration of PGN up to 24 h after stimulation. Phosphorylation of MAPKs and IB is inhibited after the second PGN stimulation in tolerant cells. Kinase activity of IRAK-1 and association between IRAK-1 and MyD88 are also suppressed in PGN-induced tolerant cells. Furthermore, down-regulation of IRAK-M expression by small interfering RNAs specific for IRAK-M reinstates the production of TNF- after PGN restimulation. These results suggest that induction of IRAK-M and inhibition of kinase activity of IRAK-1 are crucial to PGN-induced tolerance in macrophages.

Received for publication, August 5, 2003 , and in revised form, December 2, 2003.

^* This work was supported in part by a grant-in-aid for scientific research (to Y. O.) from the Japanese Ministry of Education, Culture, Sports, Science and Technology. 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: Dept. of Infectious Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel.: 81-3-3815-5411; Fax: 81-3-5800-8805; E-mail: yasuota-tky{at}umin.ac.jp.

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