Loss of Caspase-8 Protects Mice Against Inflammation-Related Hepatocarcinogenesis but Induces Non-Apoptotic Liver Injury
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2011
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Elsevier
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Liedtke C, Bangen JM, Freimuth J, Beraza N, Lambertz D, Cubero FJ, Hatting M, Karlmark KR, Streetz KL, Krombach GA, Tacke F, Gassler N, Riethmacher D, Trautwein C. Loss of caspase-8 protects mice against inflammation-related hepatocarcinogenesis but induces non-apoptotic liver injury. Gastroenterology. 2011 Dec;141(6):2176-87. doi: 10.1053/j.gastro.2011.08.037. Epub 2011 Aug 28. PMID: 21878202.
Abstract
BACKGROUND & AIMS: Disruption of the nuclear factor-kB (NF-kB) essential modulator (NEMO) in hepatocytesof mice (NEMOAhepa mice) results in spontaneous liver
apoptosis 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 after
induction 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 steatosis
and hepatocarcinogenesis but had a separate, spontaneous phenotype that included massive liver necrosis, cholestasis, and biliary lesions. The common mechanism by which inactivation
of 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 by
Casp8, 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-mediated
necrosis in an inflammatory environment.
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*Department of Medicine III, University Hospital, Aachen, Germany;
‡Department of Radiology, Justus-Liebig University, Giessen, Germany;
§Institute of Pathology, University Hospital Aachen, Germany; and
Human Genetics Division, University of Southampton, Southampton General Hospital, Southampton, United Kingdom