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Molecular basis for lipopolysaccharide mimetic action of Taxol^TM and flavolipin

Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Toyama, Tokyo, Japan

Kazunori Gomi

Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Toyama, Tokyo, Japan

Yohko Kawai

Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Toyama, Tokyo, Japan

Masao Shiozaki

Exploratory Chemistry Research Laboratories, Sankyo Company, Limited, Tokyo, Japan

Masahiro Nishijima

Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Toyama, Tokyo, Japan, nishim{at}nih.go.jp

We previously reported that Taxol^TM, which mimics the action of LPS on murine macrophages, induces signals via mouse TLR4/MD-2, but not via human TLR4/MD-2. Here we investigated the molecular basis for this species-specific action of Taxol^TM. Expression of mouse MD-2 conferred both LPS and Taxol^TM responsiveness on HEK293 cells expressing mouse TLR4, whereas expression of human MD-2 conferred LPS responsiveness alone, suggesting that MD-2 is responsible for the species-specificity of Taxol^TM responsiveness. Furthermore, mouse MD-2 mutants, in which Gln-22 was changed to other amino acids, showed dramatically reduced ability to confer Taxol^TM responsiveness, although their ability to confer LPS responsiveness was not affected. These results indicated that Gln-22 of mouse MD-2 is essential for Taxol^TM signaling, but not for LPS signaling. In this study, we also found that the TLR4/MD-2 complex, together with CD14, mediated signal transduction induced by flavolipin, an amino acid-containing lipid unique to Flavobacterium meningosepticum.

Journal of Endotoxin Research, Vol. 9, No. 5, 301-307 (2003)
DOI: 10.1177/09680519030090050501


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