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 Javier; Hatting, Maximilian; Karlmark, Karlin Raja; Streetz, Konrad L.; Krombach, Gabriele A.; Tacke, Frank; Gaßler, Nikolaus; Riethmacher, Dieter

doi:10.1053/j.gastro.2011.08.037

Cited by 102 publications

(101 citation statements)

References 30 publications

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“…In addition, LPC-specific knockout of caspase-8 could prevent hepatocyte apoptosis and HCC development in NEMO LPC-KO mice. 28 However, whereas caspase-8 deficiency caused massive necrotic hepatocyte death in NEMO LPC-KO mice resulting in severe cholestatic liver disease, 28 we found that FADD deficiency caused only very mild focal hepatocyte necrosis without any signs of biliary damage and cholestasis. This difference could reflect different functions of FADD and caspase-8 in regulating necrotic hepatocyte death, or alternatively a different health status of the mice considering that commensal or opportunistic microorganisms could be involved in triggering necrosis of hepatocytes.…”

Section: Discussionmentioning

confidence: 67%

“…15 In addition, LPCspecific knockout of caspase-8 inhibited spontaneous hepatocyte apoptosis and HCC development in NEMO LPC-KO mice, although it caused non-apoptotic hepatocyte death and cholestasis. 17 Given the essential role of FADD and caspase-8 in mediating apoptosis downstream of death receptors, 16 we hypothesized that death receptor-mediated apoptosis of NEMO-deficient hepatocytes drives the development of hepatitis and HCC in NEMO LPC-KO mice. The three main death receptors of the TNF receptor superfamily that are capable of inducing caspase-8-mediated apoptosis are TNFR1, Fas/CD95 and TRAIL-R/DR5.…”

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confidence: 99%

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Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

et al. 2014

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Hepatocellular carcinoma (HCC) usually develops in the context of chronic hepatitis triggered by viruses or toxic substances causing hepatocyte death, inflammation and compensatory proliferation of liver cells. Death receptors of the TNFR superfamily regulate cell death and inflammation and are implicated in liver disease and cancer. Liver parenchymal cell-specific ablation of NEMO/IKKc, a subunit of the IjB kinase (IKK) complex that is essential for the activation of canonical NF-jB signalling, sensitized hepatocytes to apoptosis and caused the spontaneous development of chronic hepatitis and HCC in mice. Here we show that hepatitis and HCC development in NEMO LPC-KO mice is triggered by death receptor-independent FADD-mediated hepatocyte apoptosis. TNF deficiency in all cells or conditional LPC-specific ablation of TNFR1, Fas or TRAIL-R did not prevent hepatocyte apoptosis, hepatitis and HCC development in NEMO LPC-KO mice. To address potential functional redundancies between death receptors we generated and analysed NEMO LPC-KO mice with combined LPC-specific deficiency of TNFR1, Fas and TRAIL-R and found that also simultaneous lack of all three death receptors did not prevent hepatocyte apoptosis, chronic hepatitis and HCC development. However, LPC-specific combined deficiency in TNFR1, Fas and TRAIL-R protected the NEMOdeficient liver from LPS-induced liver failure, showing that different mechanisms trigger spontaneous and LPS-induced hepatocyte apoptosis in NEMO LPC-KO mice. In addition, NK cell depletion did not prevent liver damage and hepatitis. Moreover, NEMO LPC-KO mice crossed into a RAG-1-deficient genetic background-developed hepatitis and HCC. Collectively, these results show that the spontaneous development of hepatocyte apoptosis, chronic hepatitis and HCC in NEMO LPC-KO mice occurs independently of death receptor signalling, NK cells and B and T lymphocytes, arguing against an immunological trigger as the critical stimulus driving hepatocarcinogenesis in this model.

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Section: Discussionmentioning

confidence: 67%

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confidence: 99%

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

et al. 2014

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“…13 Loss of Casp8 in Nemo Dhepa mice prevents liver apoptosis and disease progression. 9 As TNF receptor family members are upstream mediators of Casp8-dependent apoptosis, we aimed to define death receptors critically involved in mediating the function of IKKg/Nemo in cell death. Thus, we tested the relevance of the TNFR1 pathway for disease progression by generating Nemo Dhepa /TNFR1 À / À doubleknockout mice and compared them with Nemo Dhepa /TRAIL À / À and Nemo Dhepa mice.…”

Section: Resultsmentioning

confidence: 99%

TNFR1 determines progression of chronic liver injury in the IKKγ/Nemo genetic model

et al. 2013

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Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral and alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, as well as cancer. Deletion of NF-jB essential modulator in hepatocytes (IKKc/Nemo) causes spontaneous progression of TNF-mediated chronic hepatitis to hepatocellular carcinoma (HCC). Thus, we analyzed the role of death receptors including TNFR1 and TRAIL in the regulation of cell death and the progression of liver injury in IKKc/Nemo-deleted livers. We crossed hepatocyte-specific IKKc/Nemo knockout mice (Nemo Dhepa ) with constitutive TNFR1 À / À and TRAIL À / À mice. Deletion of TNFR1, but not TRAIL, decreased apoptotic cell death, compensatory proliferation, liver fibrogenesis, infiltration of immune cells as well as pro-inflammatory cytokines, and indicators of tumor growth during the progression of chronic liver injury. These events were associated with diminished JNK activation. In contrast, deletion of TNFR1 in bone-marrow-derived cells promoted chronic liver injury. Our data demonstrate that TNF-and not TRAIL signaling determines the progression of IKKc/Nemo-dependent chronic hepatitis. Additionally, we show that TNFR1 in hepatocytes and immune cells have different roles in chronic liver injury-a finding that has direct implications for treating chronic liver disease.

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“…Following acute infection and an acute inflammatory response, caspase-1 induces cell death by pyroptosis New functions for old molecules S Shalini et al necrosis-mediated liver injury. 74 In addition, conditional deletion of caspase-8 in epidermal keratinocytes, is associated with chronic skin inflammatory disease associated with constitutive IRF3 signaling. 72 Interestingly, this role for caspase-8 in suppressing inflammation is independent of signaling mediated through TNF, IL-1β or TLR receptors and independent of NFκβ signaling.…”

Section: Caspases In Inflammation and Immunitymentioning

confidence: 99%

“…Hepatocyte-specific deletion of caspase-8 (Casp8 Δhepa ) was found to be protective against hepatocarcinogenesis in NEMO Δhepa mice that develop spontaneous HCC. 74 Thus caspase-8-induced apoptosis and compensatory proliferation is important in HCC progression, but the increased necrosis and liver damage observed in the absence of caspase-8, is insufficient for tumor progression.…”

Section: Caspases In Tumorigenesismentioning

confidence: 99%

Old, new and emerging functions of caspases

et al. 2014

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Caspases are proteases with a well-defined role in apoptosis. However, increasing evidence indicates multiple functions of caspases outside apoptosis. Caspase-1 and caspase-11 have roles in inflammation and mediating inflammatory cell death by pyroptosis. Similarly, caspase-8 has dual role in cell death, mediating both receptor-mediated apoptosis and in its absence, necroptosis. Caspase-8 also functions in maintenance and homeostasis of the adult T-cell population. Caspase-3 has important roles in tissue differentiation, regeneration and neural development in ways that are distinct and do not involve any apoptotic activity. Several other caspases have demonstrated anti-tumor roles. Notable among them are caspase-2, -8 and -14. However, increased caspase-2 and -8 expression in certain types of tumor has also been linked to promoting tumorigenesis. Increased levels of caspase-3 in tumor cells causes apoptosis and secretion of paracrine factors that promotes compensatory proliferation in surrounding normal tissues, tumor cell repopulation and presents a barrier for effective therapeutic strategies. Besides this caspase-2 has emerged as a unique caspase with potential roles in maintaining genomic stability, metabolism, autophagy and aging. The present review focuses on some of these less studied and emerging functions of mammalian caspases.

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Loss of Caspase-8 Protects Mice Against Inflammation-Related Hepatocarcinogenesis but Induces Non-Apoptotic Liver Injury

Cited by 102 publications

References 30 publications

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

TNFR1 determines progression of chronic liver injury in the IKKγ/Nemo genetic model

Old, new and emerging functions of caspases

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