title: Liver injury induced by lipopolysaccharide is mediated by TNFR-1 but not by TNFR-2 or Fas in mice.
abstract: Endotoxemia causes liver injury in which tumor necrosis factor (TNF)-alpha plays a significant role by inducing hepatic apoptosis. We here examined if such apoptosis is strictly dependent on TNF-alpha and which type of TNF receptor (TNFR) is involved, employing TNFR-1- and -2-knockout mice. Lipopolysaccharide (LPS) dose-dependently induced liver injury in both wild-type (WT) and TNFR-2-knockout mice as indicated by plasma ALT activities, whereas the injury was absent in TNFR-1-knockout mice. Similarly, apoptotic hepatocyte death was observed in WT and TNFR-2-knockout mice after LPS-injection, but not in TNFR-1-knockout mice. Plasma levels of TNF-alpha, interleukin (IL)-6, IL-10 and interferon-gamma as well as hepatic TNF-alpha levels increased equally in mice with either genotype after LPS-injection. LPS also enhanced equally the mRNA expression of Fas but not Fas ligand irrespective of either genotype, as measured by RNase protection assay. These findings suggest that apoptotic liver injury induced by LPS depends on TNF-alpha signaling through TNFR-1 but not via TNFR-2 or Fas-Fas ligand pathway.
authors.affiliation: Department of Internal Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Shimizu
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamada
authors.forename: Masataka
authors.initials: M
authors.lastname: Okuno
authors.forename: Hiroo
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Osawa
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki