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Cutting Edge: Endotoxin Tolerance in Mouse Peritoneal Macrophages Correlates with Down-Regulation of Surface Toll-Like Receptor 4 Expression¹

Fumiko Nomura^*,,§, Sachiko Akashi, Yoshimitsu Sakao^*,§, Shintaro Sato^*,§, Taro Kawai^*,§, Makoto Matsumoto^*,§, Kenji Nakanishi^,§, Masao Kimoto, Kensuke Miyake, Kiyoshi Takeda^*,§ and Shizuo Akira^2,*,§

^* Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; Department of Immunology and Medical Zoology, Hyogo College of Medicine, Hyogo, Japan; Department of Immunology, Saga Medical School, Saga, Japan; and ^§ Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan

Monocytes/macrophages exposed to LPS show reduced responses to second stimulation with LPS, which is termed LPS tolerance. In this study, we investigated molecular mechanism of LPS tolerance in macrophages. Mouse peritoneal macrophages pre-exposed to LPS exhibited reduced production of inflammatory cytokines in a time- and dose-dependent manner. Activation of neither IL-1 receptor-associated kinase nor NF-B was observed in macrophages that became tolerant by LPS pretreatment, indicating that the proximal event in Toll-like receptor 4 (TLR4)-MyD88-dependent signaling is affected in tolerant macrophages. Although TLR4 mRNA expression significantly decreased within a few hours of LPS pretreatment and returned to the original level at 24 h, the surface TLR4 expression began to decrease within 1 h, with a gradual decrease after that, and remained suppressed over 24 h. A decrease in inflammatory cytokine production in tolerant macrophages well correlates with down-regulation of the surface TLR4 expression, which may explain one of the mechanisms for LPS tolerance.