Agonistic antibody to TLR4/MD-2 protects mice from acute lethal hepatitis induced by TNF-alpha.
LPS is recognized by a heterodimer consisting of TLR4 and its coreceptor MD-2. LPS signal causes excessive inflammation and tissue damage. In this study, we show that a mAb to TLR4/MD-2 protected mice from acute lethal hepatitis caused by LPS/d-galactosamine. The protective effect of the mAb was not due to inhibition of LPS response, because serum TNF-alpha, which was induced by LPS and caused lethal hepatitis, was 10 times up-regulated by the mAb pretreatment. Moreover, this mAb induced antiapoptotic genes in liver in a TLR4/MD-2-dependent manner. These results demonstrated that an agonistic mAb to TLR4/MD-2 protected mice from LPS/d-galactosamine-induced acute lethal hepatitis by delivering a protective signal activating NF-kappaB through TLR4/MD-2.
Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Japan.
Sachiko
S
Akashi-Takamura
Takahisa
T
Furuta
Koichiro
K
Takahashi
Natsuko
N
Tanimura
Yutaka
Y
Kusumoto
Toshihiko
T
Kobayashi
Shin-Ichiroh
S
Saitoh
Yoshiyuki
Y
Adachi
Takahiro
T
Doi
Kensuke
K
Miyake
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology; D002460:Cell Line; D000939:Epitopes / Q000276:immunology; D005688:Galactosamine / Q000494:pharmacology; D006505:Hepatitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051218:Lymphocyte Antigen 96 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D012772:Shock, Septic / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000939:Epitopes; D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine