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

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

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Background & Aims: Disruption of the nuclear factor-κB (NF-κB) essential modulator (NEMO) in hepatocytes of mice (NEMO Δhepa 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 Δhepa mice or after induction of acute liver injury. Methods: We created mice with conditional deletion of Casp8 in hepatocytes (Casp8 Δhepa) and Casp8 ΔhepaNEMO Δhepa 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 ΔhepaNEMO Δhepa 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 RIP3these 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.

Original languageEnglish
Pages (from-to)2176-2187
Number of pages12
JournalGastroenterology
Volume141
Issue number6
DOIs
Publication statusPublished - Dec 2011
Externally publishedYes

Fingerprint

Caspase 8
Inflammation
Liver
Wounds and Injuries
Receptor-Interacting Protein Serine-Threonine Kinases
Necrosis
Hepatocytes
Apoptosis
Death Domain Receptors
Concanavalin A
Proteins
Cholestasis
Knockout Mice
Lipopolysaccharides
Liver Diseases
Hepatocellular Carcinoma
Fibrosis
Peptide Hydrolases
Chronic Disease
Phosphotransferases

Keywords

  • FADD
  • Fas-associated Protein With Death Domain
  • Inflammation
  • TNF Signaling
  • Tumor Necrosis Factor

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Liedtke, C., Bangen, J. M., Freimuth, J., Beraza, N., Lambertz, D., Cubero, F. J., ... Trautwein, C. (2011). Loss of caspase-8 protects mice against inflammation-related hepatocarcinogenesis but induces non-apoptotic liver injury. Gastroenterology, 141(6), 2176-2187. https://doi.org/10.1053/j.gastro.2011.08.037

Loss of caspase-8 protects mice against inflammation-related hepatocarcinogenesis but induces non-apoptotic liver injury. / 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; Trautwein, Christian.

In: Gastroenterology, Vol. 141, No. 6, 12.2011, p. 2176-2187.

Research output: Contribution to journalArticle

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 2011, 'Loss of caspase-8 protects mice against inflammation-related hepatocarcinogenesis but induces non-apoptotic liver injury', Gastroenterology, vol. 141, no. 6, pp. 2176-2187. https://doi.org/10.1053/j.gastro.2011.08.037
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 ; Trautwein, Christian. / Loss of caspase-8 protects mice against inflammation-related hepatocarcinogenesis but induces non-apoptotic liver injury. In: Gastroenterology. 2011 ; Vol. 141, No. 6. pp. 2176-2187.
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AU - Bangen, Jörg Martin

AU - Freimuth, Julia

AU - Beraza, Naiara

AU - Lambertz, Daniela

AU - Cubero, Francisco J.

AU - Hatting, Maximilian

AU - Karlmark, Karlin R.

AU - Streetz, Konrad L.

AU - Krombach, Gabriele A.

AU - Tacke, Frank

AU - Gassler, Nikolaus

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AU - Trautwein, Christian

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