title: Ligand-dependent Toll-like receptor 4 (TLR4)-oligomerization is directly linked with TLR4-signaling.
abstract: 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.
authors.affiliation: Division of Infectious Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Shin-ichiroh
authors.initials: S
authors.lastname: Saitoh
authors.forename: Sachiko
authors.initials: S
authors.lastname: Akashi
authors.forename: Takenao
authors.initials: T
authors.lastname: Yamada
authors.forename: Natsuko
authors.initials: N
authors.lastname: Tanimura
authors.forename: Fumi
authors.initials: F
authors.lastname: Matsumoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukase
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kusumoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kosugi
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism* / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism* / Q000494:pharmacology*; D004926:Escherichia coli / Q000472:pathogenicity; D008024:Ligands; D008070:Lipopolysaccharides / Q000633:toxicity*; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection
chemical_list: D000954:Antigens, Surface; D002352:Carrier Proteins; D008024:Ligands; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors