%0 Journal Article
%A Liedtke, Christian
%A Cubero Palero, Francisco Javier
%A Trautwein, Christian
%T Loss of Caspase-8 Protects Mice Against Inflammation-Related Hepatocarcinogenesis but Induces Non-Apoptotic Liver Injury
%D 2011
%@ 0016-5085
%U https://hdl.handle.net/20.500.14352/97655
%X BACKGROUND & AIMS: Disruption of the nuclear factor-kB (NF-kB) essential modulator (NEMO) in hepatocytesof mice (NEMOAhepa mice) results in spontaneous liverapoptosis and chronic liver disease involving inflammation, steatosis, fibrosis, and development of hepatocellular carcinoma. Activation of caspase-8 (Casp8) initiates death receptor-mediated apoptosis. We investigated the pathogenic role of this protease in NEMOAhepa mice or afterinduction of acute liver injury. METHODS: We created mice with conditional deletion of Casp8 in hepatocytes(Casp8Ahepa) and Casp8AhepaNEMOAhepa double knockout mice. Acute liver injury was induced by Fas-activating antibodies, lipopolysaccharides, or concanavalin A. Spontaneous hepatocarcinogenesis was monitored by magnetic resonance imaging. RESULTS: Hepatocyte-specific deletion of Casp8 protected mice from induction of apoptosis and liver injury by Fas or lipopolysaccharides but increased necrotic damage and reduced survival times of mice given concanavalin A. Casp8AhepaNEMOAhepa mice were protected against steatosisand hepatocarcinogenesis but had a separate, spontaneous phenotype that included massive liver necrosis, cholestasis, and biliary lesions. The common mechanism by which inactivationof Casp8 induces liver necrosis in both injury models involves the formation of protein complexes that included the adaptor protein Fas-associated protein with death domain and the kinases receptor-interacting protein (RIP) 1 and RIP3—these have been shown to be required for programmed necrosis. We demonstrated that hepatic RIP1 was proteolytically cleaved byCasp8, whereas Casp8 inhibition resulted in accumulation of RIP complexes and subsequent liver necrosis. CONCLUSIONS: Inhibition of Casp8 protects mice from hepatocarcinogenesis following chronic liver injury mediated by apoptosis of hepatocytes but can activate RIP-mediatednecrosis in an inflammatory environment.
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