| Literature DB >> 15906084 |
Hideki Fujii1, Shuichi Seki, Sawako Kobayashi, Takuya Kitada, Nobuyoshi Kawakita, Keishi Adachi, Hiroko Tsutsui, Kenji Nakanishi, Hiromi Fujiwara, Yoshinori Ikarashi, Masaru Taniguchi, Mitchell Kronenberg, Kronenberg Mitchell, Masaru Ikemoto, Yuji Nakajima, Tetsuo Arakawa, Kenji Kaneda.
Abstract
Natural killer-T (NKT) cells are rich in the liver. However, their involvement in liver injury is not fully understood. We developed here a new murine model of NKT-cell-activation-associated liver injury, and investigated a role of tumor necrosis factor alpha (TNF-alpha) and Fas in pathogenesis. We injected intraperitoneally alpha-galactosylceramide (alpha-GalCer), an NKT-cell stimulant, into D-galactosamine (GalN)-sensitized mice. Survival rate, pathological changes of the liver, and plasma concentrations of cytokines were studied. Alpha-GalCer/GalN administration gave a lethal effect within 7 h, making pathological changes such as massive parenchymal hemorrhage, hepatocyte apoptosis, sinusoidal endothelial cell injury, and close apposition of lymphocytes to apoptotic hepatocytes. Anti-NK1.1 mAb-pretreated mice and Valpha14NKT knock out (KO) mice did not develop liver injury. Tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were elevated at 4 h in the plasma. These cytokines were produced by hepatic lymphocytes as demonstrated by in vitro stimulation with alpha-GalCer. The lethal effect was suppressed in TNF-alpha KO mice, TNF receptor-1 KO mice, and lpr/lpr (Fas deficient) mice, whereas it was not in IFN-gamma KO mice. These results indicate that the present liver injury is characterized by parenchymal hemorrhage and hepatocyte apoptosis, and mediated by TNF-alpha secretion and direct cytotoxicity of alpha-GalCer-activated NKT cells.Entities:
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Year: 2005 PMID： 15906084 DOI： 10.1007/s00428-005-1265-8
Source DB: PubMed Journal: Virchows Arch ISSN： 0945-6317 Impact factor: 4.064