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Cutting Edge: Cell Surface Expression and Lipopolysaccharide Signaling Via the Toll-Like Receptor 4-MD-2 Complex on Mouse Peritoneal Macrophages¹

Sachiko Akashi^*, Rintaro Shimazu^*, Hirotaka Ogata^*, Yoshinori Nagai^*, Kiyoshi Takeda, Masao Kimoto^* and Kensuke Miyake^2,*

^* Department of Immunology, Saga Medical School, Nabeshima, Japan; and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

The human MD-2 molecule is associated with the extracellular domain of human Toll-like receptor 4 (TLR4) and greatly enhances its LPS signaling. The human TLR4-MD-2 complex thus signals the presence of LPS. Little is known, however, about cell surface expression and LPS signaling of the TLR4-MD-2 complex in vivo. We cloned mouse MD-2 molecularly and established a unique mAb MTS510, which reacted selectively with mouse TLR4-MD-2 but not with TLR4 alone in flow cytometry. Mouse MD-2 expression in TLR4-expressing cells enhanced LPS-induced NF-B activation, which was clearly inhibited by MTS510. Thioglycolate-elicited peritoneal macrophages expressed TLR4-MD-2, which was rapidly down-regulated in the presence of LPS. Moreover, LPS-induced TNF- production by peritoneal macrophages was inhibited by MTS510. Collectively, the TLR4-MD-2 complex is expressed on macrophages in vivo and senses and signals the presence of LPS.