Essential role of MD-2 in LPS responsiveness and TLR4 distribution.
Toll-like receptor 4 (TLR4) mediates lipopolysaccharide (LPS) signaling in a variety of cell types. MD-2 is associated with the extracellular domain of TLR4 and augments TLR4-dependent LPS responses in vitro. We show here that MD-2(-/-) mice do not respond to LPS, do survive endotoxic shock but are susceptible to Salmonella typhimurium infection. We found that in MD-2(-/-) embryonic fibroblasts, TLR4 was not able to reach the plasma membrane and predominantly resided in the Golgi apparatus, whereas TLR4 was distributed at the leading edge surface of cells in wild-type embryonic fibroblasts. Thus, MD-2 is essential for correct intracellular distribution and LPS-recognition of TLR4.
Nagai
Yoshinori
Y
Division of Infectious Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Akashi
Sachiko
S
Nagafuku
Masakazu
M
Ogata
Masato
M
Iwakura
Yoichiro
Y
Akira
Shizuo
S
Kitamura
Toshio
T
Kosugi
Atsushi
A
Kimoto
Masao
M
Miyake
Kensuke
K
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D029721:Drosophila Proteins; D005260:Female; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000276:immunology; D008050:Lipid A / Q000276:immunology* / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D051218:Lymphocyte Antigen 96; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000276:immunology*; D012480:Salmonella Infections / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology; D012772:Shock, Septic / Q000276:immunology; D013154:Spleen / Q000166:cytology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000954:Antigens, Surface; D029721:Drosophila Proteins; D015850:Interleukin-6; D008050:Lipid A; D018950:Lipopolysaccharide Receptors; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12