Human MD-2 confers on mouse Toll-like receptor 4 species-specific lipopolysaccharide recognition.
Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide (LPS). MD-2 is associated with TLR4 and imparts LPS responsiveness to it. Little is known, however, as to whether MD-2 directly regulates LPS recognition by TLR4. To address the issue, we took advantage of a species-specific pharmacology of lipid IVa, an analogue of lipid A. Lipid IVa acted agonistically on mouse (m) TLR4/MD-2 but not on human (h) TLR4/MD-2. Lipid IVa antagonized the agonistic effect of lipid A on hTLR4/MD-2. We examined the chimeric complex consisting of mTLR4 and hMD-2 to ask whether species specificity is conferred by TLR4 or MD-2. hMD-2 was clearly distinct from mMD-2 in the way of influencing LPS recognition by mTLR4. hMD-2 conferred on mTLR4 responsiveness to lipid A but not to lipid IVa. Moreover, lipid IVa acted as a lipid A antagonist on mTLR4 that is associated with hMD-2. Collectively, MD-2 directly influences the fine specificity of TLR4.
Akashi
S
S
Department of Immunology, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan.
Nagai
Y
Y
Ogata
H
H
Oikawa
M
M
Fukase
K
K
Kusumoto
S
S
Kawasaki
K
K
Nishijima
M
M
Hayashi
S
S
Kimoto
M
M
Miyake
K
K
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D029721:Drosophila Proteins; D006017:Glycolipids / Q000494:pharmacology; D006801:Humans; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000378:metabolism* / Q000494:pharmacology; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection
D000276:Adjuvants, Immunologic; D000954:Antigens, Surface; D029721:Drosophila Proteins; D006017:Glycolipids; C495377:LY96 protein, human; D008050:Lipid A; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C040142:lipid A precursors, bacterial