RRC ID 39608
Author Kawasaki K, Akashi S, Shimazu R, Yoshida T, Miyake K, Nishijima M.
Title Mouse toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol.
Journal J. Biol. Chem.
Abstract Taxol, an antitumor agent derived from a plant, mimics the action of lipopolysaccharide (LPS) in mice but not in humans. Although Taxol is structurally unrelated to LPS, Taxol and LPS are presumed to share a receptor or signaling molecule. 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. To determine whether TLR4.MD-2 complex mediates a Taxol-induced signal, we constructed 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, and then examined whether Taxol induced NFkappaB activation in these transfectants. Noticeable NFkappaB activation by Taxol was detected in Ba/F3 expressing mouse TLR4 and mouse MD-2 but not in the other transfectants. Coexpression of human TLR4 and human MD-2 did not confer Taxol responsiveness on Ba/F3 cells, suggesting that the TLR4. MD-2 complex is responsible for the species specificity with respect to Taxol responsiveness. Furthermore, Taxol-induced NFkappaB activation via TLR4.MD-2 was blocked by an LPS antagonist that blocks LPS-induced NFkappaB activation via TLR4.MD-2. These results demonstrated that coexpression of mouse TLR4 and mouse MD-2 is required for Taxol responsiveness and that the TLR4.MD-2 complex is the shared molecule in Taxol and LPS signal transduction in mice.
Volume 275(4)
Pages 2251-4
Published 2000-1-28
DOI 10.1074/jbc.275.4.2251
PMID 10644670
MeSH Animals Blood Drosophila Proteins* Humans Lipopolysaccharides / antagonists & inhibitors Lipopolysaccharides / metabolism* Membrane Glycoproteins / physiology* Mice Mice, Inbred C3H Molecular Mimicry NF-kappa B / metabolism Paclitaxel / metabolism* Paclitaxel / pharmacology Receptors, Cell Surface / physiology* Signal Transduction / drug effects Signal Transduction / physiology* Toll-Like Receptor 4 Toll-Like Receptors
IF 4.106
Times Cited 256
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
Human and Animal Cells