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Involvement of TLR4/MD-2 complex in species-specific lipopolysaccharide-mimetic signal transduction by Taxol

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

Sachiko Akashi

Department of Immunology, Saga Medical School, Nabeshima, Saga, Japan

Rintaro Shimazu

Department of Immunology, Saga Medical School, Nabeshima, Saga, Japan

Takashi Yoshida

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

Kensuke Miyake

Department of Immunology, Saga Medical School, Nabeshima, Saga, Japan

Masahiro Nishijima

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

Taxol, an antitumor agent derived from a plant, mimics the action of lipopolysaccharide (LPS) in mice, but not in humans. The LPS-mimetic activity of Taxol is not observed in LPS-hyporesponsive C3H/HeJ mice which possess a point mutation in Toll-like receptor 4 (TLR4); therefore, TLR4 appears to be involved in both Taxol and LPS signaling. In addition, TLR4 was recently shown to physically associate with MD-2, a molecule that confers LPS-responsiveness on TLR4. Here we examined whether or not TLR4/MD-2 complex mediates a Taxol-induced signal by using transformants of the mouse pro-B cell line, Ba/F3, expressing mouse TLR4 alone, both mouse TLR4 and mouse MD-2, and both mouse MD-2 and mouse TLR4 lacking the cytoplasmic portion. Our results demonstrated that co-expression of mouse TLR4 and mouse MD-2 was required for Taxol responsiveness, and that the TLR4/MD-2 complex is the shared molecule in Taxol and LPS signal transduction in mice. We also found that mouse MD-2, but not human MD-2, is involved in Taxol signaling, suggesting that MD-2 is responsible for the species-specific responsiveness to Taxol.

Journal of Endotoxin Research, Vol. 7, No. 3, 232-236 (2001)
DOI: 10.1177/09680519010070030701


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