Ligand-dependent Toll-like receptor 4 (TLR4)-oligomerization is directly linked with TLR4-signaling.
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.
Saitoh
Shin-ichiroh
S
Division of Infectious Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Akashi
Sachiko
S
Yamada
Takenao
T
Tanimura
Natsuko
N
Matsumoto
Fumi
F
Fukase
Koichi
K
Kusumoto
Shoichi
S
Kosugi
Atsushi
A
Miyake
Kensuke
K
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
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