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Loss of caspase-8 protects mice against inflammation-related hepatocarcinogenesis but induces non-apoptotic liver injury

Record type: Article

BACKGROUND
AIMS: Disruption of the nuclear factor-?B (NF-?B) essential modulator (NEMO) in hepatocytes of mice (NEMO(?hepa) 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 NEMO(?hepa) mice or after induction of acute liver injury.
METHODS:We created mice with conditional deletion of Casp8 in hepatocytes (Casp8(?hepa)) and Casp8(?hepa)NEMO(?hepa) 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. Casp8(?hepa)NEMO(?hepa) 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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Citation

Liedtke, Christian, Bangen, Jörg–Martin, Freimuth, Julia, Beraza, Naiara, Lambertz, Daniela, Cubero, Francisco J., Hatting, Maximilian, Karlmark, Karlin R., Streetz, Konrad L., Krombach, Gabriele A., Tacke, Frank, Gassler, Nikolaus, Riethmacher, Dieter and Trautwein, Christian (2011) Loss of caspase-8 protects mice against inflammation-related hepatocarcinogenesis but induces non-apoptotic liver injury Gastroenterology, 141, (6), pp. 2176-2187. (doi:10.1053/j.gastro.2011.08.037).

More information

Accepted/In Press date: 26 August 2011
Published date: December 2011
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 204059
URI: http://eprints.soton.ac.uk/id/eprint/204059
ISSN: 0016-5085
PURE UUID: dbdbe596-c392-4877-a61e-d7b3bed0f924

Catalogue record

Date deposited: 23 Nov 2011 12:03
Last modified: 18 Jul 2017 11:07

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Contributors

Author: Christian Liedtke
Author: Jörg–Martin Bangen
Author: Julia Freimuth
Author: Naiara Beraza
Author: Daniela Lambertz
Author: Francisco J. Cubero
Author: Maximilian Hatting
Author: Karlin R. Karlmark
Author: Konrad L. Streetz
Author: Gabriele A. Krombach
Author: Frank Tacke
Author: Nikolaus Gassler
Author: Christian Trautwein

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