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Ligand-dependent Toll-like receptor 4 (TLR4)-oligomerization is directly linked with TLR4-signaling

Division of Infectious Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Sachiko Akashi

Division of Infectious Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Takenao Yamada

Department of Medical Technology and Science, Osaka University, Osaka, Japan

Natsuko Tanimura

Department of Medical Technology and Science, Osaka University, Osaka, Japan

Fumi Matsumoto

Department of Medical Technology and Science, Osaka University, Osaka, Japan

Koichi Fukase

Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan

Shoichi Kusumoto

Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan

Atsushi Kosugi

Department of Medical Technology and Science, Osaka University, Osaka, Japan, CREST, Japan Science and Technology Corporation, Tokyo, Japan

Kensuke Miyake

Division of Infectious Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan, kmiyake{at}ims.u-tokyo.ac.jp, CREST, Japan Science and Technology Corporation, Tokyo, Japan

Toll-like receptor 4 (TLR4) and MD-2 recognize lipid A, the active moiety of microbial lipopolysaccharide (LPS). Little is known about mechanisms for LPS recognition by TLR4/MD-2. We here showed, by using in vitro transfectants, ligand-induced TLR4-oligomerization, which required both membrane CD14 and MD-2. We previously reported that lipid IVa, a lipid A precursor, is agonistic on mouse TLR4/MD-2 but antagonistic on human TLR4/MD-2 and chimeric mouse TLR4/human MD-2. Lipid IVa triggered oligomerization of mouse TLR4/MD-2 but not human TLR4/MD-2 or chimeric mouse TLR4/human MD-2. Further, lipid IVa inhibited lipid A-dependent oligomerization of chimeric mouse TLR4/human MD-2. These results demonstrate that ligand-induced TLR4-oligomerization is directly linked with TLR4-signaling and suggest that MD-2 has an important role in regulating TLR4-oligomerization.

Key Words: Innate immunity • Toll-like receptor • lipopolysaccharide

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