title: Toll-like receptor 4-MD-2 complex mediates the signal transduction induced by flavolipin, an amino acid-containing lipid unique to Flavobacterium meningosepticum.
abstract: Flavolipin, an amino acid-containing lipid isolated from Flavobacterium meningosepticum, induces many immune responses. It has been shown that flavolipin does not induce an immune response of macrophages derived from C3H/HeJ mice, which possess a point mutation in Toll-like receptor 4 (TLR4). To determine whether TLR4 or the molecular complex of TLR4 and TLR4 association molecule MD-2 mediates the flavolipin signal, flavolipin responsiveness was examined by measuring NF-kappaB activation in Ba/F3 cells and Ba/F3 transfectants expressing TLR4 or both TLR4 and MD-2. Flavolipin-induced NF-kappaB activation was detected in the cells expressing both TLR4 and MD-2, but not in the other cells. Expression of CD14 in the transfectant expressing both TLR4 and MD-2 increased the sensitivity to flavolipin. Furthermore, flavolipin stereoisomers were chemically synthesized, and their abilities to induce NF-kappaB activation were examined. (R)-Flavolipin, in which the configuration of the lipid moiety is R, induced NF-kappaB activation via the TLR4-MD-2 complex, but (S)-flavolipin did not. In this study, we demonstrated the involvement of TLR4-MD-2 and CD14 in flavolipin signaling and the importance of the (R)-configuration of the flavolipin lipid moiety for the induction of an immune response via TLR4-MD-2.
authors.affiliation: Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Gomi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kawasaki
authors.forename: Yohko
authors.initials: Y
authors.lastname: Kawai
authors.forename: Masao
authors.initials: M
authors.lastname: Shiozaki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishijima
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D029721:Drosophila Proteins; D005417:Flavobacterium / Q000276:immunology*; D005998:Glycine / Q000276:immunology / Q000502:physiology*; D008055:Lipids / Q000276:immunology / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000235:genetics; D008074:Lipoproteins / Q000502:physiology*; D051218:Lymphocyte Antigen 96; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012694:Serine / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D013237:Stereoisomerism; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection
chemical_list: D000954:Antigens, Surface; D029721:Drosophila Proteins; D008055:Lipids; D018950:Lipopolysaccharide Receptors; D008074:Lipoproteins; D051218:Lymphocyte Antigen 96; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C451497:flavolipin; D012694:Serine; D005998:Glycine