Intrinsic resistance to TNF-alpha-induced hepatocyte apoptosis in ICR mice correlates with expression of a short form of c-FLIP.
The administration of tumor necrosis factor-alpha (TNF-alpha) or the anti-Fas antibody (Jo-2) to mice causes acute liver failure, which is lethal within hours as a result of the induction of apoptosis in hepatocytes. It was recently reported that nonobese diabetic (NOD) mice are less sensitive to TNF-alpha/D-galactosamine (GalN)-induced liver failure than C57BL/6J (B6) mice, whereas both NOD and B6 mice were sensitive to the lethal effect of Jo-2. In the present study, we investigated the differences between the apoptotic liver cell death induced by TNF-alpha/GalN and that induced by Jo-2. B6, NOD, and Jcl-Imperial Cancer Research (ICR) mice were injected intravenously with TNF-alpha/GalN or Jo-2. ICR mice were less sensitive to TNF-alpha/GalN-induced liver failure than NOD and B6 mice (P<0.0001). In contrast, ICR mice were more sensitive to Jo-2-induced liver failure than B6 mice (P=0.0003). The liver caspase-3, -8 activity, serum transaminase levels, and the number of apoptotic liver nuclei all decreased in ICR in comparison to B6 mice treated with TNF-alpha/GalN. The mRNA expression of TNFR-associated death domain, Fas associated protein with death domain, and Bcl family and nuclear factor-kappaB activation induced by TNF-alpha/GalN were similar in both mice. Interestingly, the short form of cellular FLICE/caspase-8-inhibitory protein (c-FLIP(S)) was constitutively upregulated in ICR mice. In conclusion, these results suggest that ICR mice have an intrinsic resistance to TNF-alpha-induced hepatocyte apoptosis, and that c-FLIP(S) may play a role in TNF-alpha/GalN-induced liver failure, but not in Fas-induced liver failure.
Takai
Shinji
S
Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan.
Nagaki
Masahito
M
Imao
Motohiro
M
Kimura
Kiminori
K
Kozawa
Osamu
O
Moriwaki
Hisataka
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005688:Galactosamine / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008813:Mice, Inbred ICR; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D061945:Caspase Inhibitors; C506387:Cflar protein, mouse; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine