Tumor necrosis factor signaling in hepatocyte apoptosis.
Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, and cancer. Our aim was to clarify the protective pathway in death receptor-mediated hepatocyte apoptosis and the significance of apoptosis in liver injury. In vitro: AdIkappaBsr plus tumor necrosis factor (TNF)-alpha/Jo2 rapidly induced apoptosis in mouse hepatocyte, whereas TNF-alpha/Jo2 alone produced little cytotoxicity. The combination of the mitochondrial permeability transition (MPT) inhibitors, cyclosporine A and trifluoperazine, protected AdIkappaBsr-infected hepatocytes from TNF-alpha- but not Fas-mediated apoptosis. The TNF-alpha and Jo2 induced iNOS through NF-kappaB. Nitric oxide donor (S-nitroso-N-acetylpenicillamine) inhibited Bid cleavage, the MPT, and caspase activation and reduced TNF-alpha- and Fas-mediated cell killing. Inhibition of PI3K by LY294,002 and a dominant-negative Akt, which attenuated NF-kappaB activation by TNF-alpha or Jo2, sensitized hepatocytes to TNF- or Jo2. In vivo: apoptosis as well as necrosis may play an important role in hepatic ischemia/reperfusion injury. Adenoviral gene transfer of myrAkt could inhibit apoptotic cell death and subsequent hepatic ischemia/reperfusion injury in the rat, through Bad not NF-kappaB. Bile acids cause liver injury during cholestasis by inducing hepatocyte apoptosis. Hepatocyte apoptosis has a major role in hepatic injury by bile duct ligation. At least, early hepatic injury by bile duct ligation involved Fas-mediated and Bcl-xL insensitive apoptotic pathway. In conclusion, the role of apoptosis in various liver diseases may suggest possible treatments.
Hatano
Etsuro
E
Department of Gastroenterological Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. etsu@kuhp.kyoto-u.ac.jp
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002463:Cell Membrane Permeability; D002867:Chromones / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D022781:Hepatocytes / Q000502:physiology*; D008107:Liver Diseases / Q000503:physiopathology; D051379:Mice; D008930:Mitochondria, Liver / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D053218:Receptors, Death Domain / Q000502:physiology; D015398:Signal Transduction; D014268:Trifluoperazine / Q000494:pharmacology; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D002867:Chromones; D009025:Morpholines; D016328:NF-kappa B; D053218:Receptors, Death Domain; D048069:Tumor Necrosis Factors; D051028:bcl-2-Associated X Protein; D014268:Trifluoperazine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D016572:Cyclosporine