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Agonistic Antibody to TLR4/MD-2 Protects Mice from Acute Lethal Hepatitis Induced by TNF-¹

Sachiko Akashi-Takamura^*,, Takahisa Furuta^*, Koichiro Takahashi^*, Natsuko Tanimura^*, Yutaka Kusumoto^*, Toshihiko Kobayashi^*, Shin-ichiroh Saitoh^*,, Yoshiyuki Adachi, Takahiro Doi and Kensuke Miyake^2,*,

^* Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Core Research for Engineering, Science, and Technology, Japan Science and Technology, Tokyo, Japan; Laboratory of Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan; and Technology and Development Team for BioSignal Program, Subteam for BioSignal Integration, RIKEN Bioresource Center, RIKEN Tsukuba Institute, Ibaraki, Japan

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-, 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-B through TLR4/MD-2.

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