Intrinsic resistance to TNF-alpha-induced hepatocyte apoptosis in ICR mice correlates with expression of a short form of c-FLIP.

Abstract

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.

• Authors: Shinji Takai, Masahito Nagaki, Motohiro Imao, Kiminori Kimura, Osamu Kozawa, Hisataka Moriwaki
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 87 Issue 6 Pg. 572-81 (Jun 2007) ISSN: 0023-6837 [Print] United States
• PMID: 17372587 (Publication Type: Journal Article)

Chemical References

• CASP8 and FADD-Like Apoptosis Regulating Protein
• Caspase Inhibitors
• Cflar protein, mouse
• Tumor Necrosis Factor-alpha
• Galactosamine

Topics

• Animals
• Apoptosis (drug effects, immunology)
• CASP8 and FADD-Like Apoptosis Regulating Protein (genetics, metabolism)
• Caspase Inhibitors
• Drug Resistance (genetics)
• Female
• Galactosamine (pharmacology)
• Hepatocytes (drug effects, enzymology, immunology, pathology)
• Mice
• Mice, Inbred ICR
• Tumor Necrosis Factor-alpha (pharmacology)