Protective role of interleukin-18 against Fas-mediated liver injury.
Interleukin (IL)-18 plays an important role in the pathogenesis of several liver diseases as well as Fas-mediated apoptosis. However, the effects of IL-18 on Fas-mediated liver injury have not been well elucidated. Therefore, we examined the effects of IL-18 on Fas-mediated apoptosis in in vitro and in vivo experiments. We found that recombinant IL-18 protected mouse hepatocellular carcinoma cell lines, BNL5, from Fas-mediated apoptosis in a dose-dependent manner with up-regulation of both nuclear factor (NF) kappaB and X-linked inhibitors of apoptosis (XIAP). IL-18 transgenic (Tg) mice were also protected from Fas-mediated liver injury and this was further confirmed by histological study and TUNEL staining. In IL-18 Tg mice, up-regulation of XIAP and down-regulation of caspase 3 were observed after injection of anti-Fas, which was consistent with the in vitro findings. These results suggest that IL-18 suppresses Fas-mediated apoptosis of hepatocytes by up-regulation of NFkappaB and XIAP, following inhibition of caspase-3 activity. This observation raises the possibility that IL-18 could be a therapeutic strategy for Fas-mediated liver injury as a negative regulator of XIAP.
Department of Gastroenterology, Mie University Graduate School of Medicine, Tsu City, Mie Prefecture, Japan.
Norihiko
N
Yamamoto
Kazumoto
K
Murata
Kentaro
K
Yoneda
Hiroyuki
H
Fuke
Yumi
Y
Yamaguchi
Keiichi
K
Ito
Kazushi
K
Sugimoto
Katsuya
K
Shiraki
Kei-Ichi
K
Yamanaka
Hitoshi
H
Mizutani
Yoshiyuki
Y
Takei
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D053222:Fas Ligand Protein / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020382:Interleukin-18 / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism*
D053222:Fas Ligand Protein; D020382:Interleukin-18; D011994:Recombinant Proteins; D019014:fas Receptor