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 language | English |
|---|---|
| Pages (from-to) | 2176-2187 |
| Number of pages | 12 |
| Journal | Gastroenterology |
| Volume | 141 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Dec 2011 |
| Externally published | Yes |
Fingerprint
Keywords
- FADD
- Fas-associated Protein With Death Domain
- Inflammation
- TNF Signaling
- Tumor Necrosis Factor
ASJC Scopus subject areas
- Gastroenterology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Loss of caspase-8 protects mice against inflammation-related hepatocarcinogenesis but induces non-apoptotic liver injury
AU - Liedtke, Christian
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
AU - Riethmacher, Dieter
AU - Trautwein, Christian
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
KW - FADD
KW - Fas-associated Protein With Death Domain
KW - Inflammation
KW - TNF Signaling
KW - Tumor Necrosis Factor
UR - http://www.scopus.com/inward/record.url?scp=81855183262&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=81855183262&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2011.08.037
DO - 10.1053/j.gastro.2011.08.037
M3 - Article
VL - 141
SP - 2176
EP - 2187
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 6
ER -