Loss of caspase-8 in hepatocytes accelerates the onset of liver regeneration in mice through premature nuclear factor kappa B activation

Freimuth, Julia; Bangen, Jörg M.; Lambertz, Daniela; Hu, Wei Shou; Nevzorova, Yulia A.; Sonntag, R; Gaßler, Nikolaus; Riethmacher, Dieter; Liedtke, Christian

doi:10.1002/hep.26538

Cited by 30 publications

(19 citation statements)

References 27 publications

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“…Our results suggest that necroptosis is prevented by caspase activity in the liver. It was already shown in mice lacking Casp8 specifically in hepatocytes (Casp8$hepa) that loss of Casp8 prevents proteolytic cleavage of RIP1 in hepatocytes (31).…”

Section: Discussionmentioning

confidence: 98%

RIP1-Dependent Programmed Necrosis is Negatively Regulated by Caspases During Hepatic Ischemia-Reperfusion

Rosentreter

Funken²,

Reifart³

et al. 2015

Shock

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Programmed necrosis (necroptosis), a newly discovered form of cell death, is mediated by receptor-interacting protein 1 (RIP1) and plays a pivotal role after myocardial, renal, and cerebral ischemia-reperfusion (I/R). The relevance of necroptosis in the postischemic liver remains, however, unclear. The aim of this study was to analyze the role of programed necrosis during hepatic I/R. C57BL6 mice were subjected to warm hepatic I/R (90 min/240 min). The animals were pretreated with either the RIP1 inhibitor necrostatin-1 (Nec-1, 3.5 μg kg) or vehicle (Nec-1inactive, 3.5 μg kg) administered systemically before ischemia. Sham-operated animals served as controls (n = 6 each group). The inflammatory response was evaluated by intravital microscopy. The hepatic transaminases alanine aminotransferase/aspartate aminotransferase in plasma as well as the activity of caspase-3 in tissue were determined as markers of hepatocellular injury. Leukocyte recruitment to the liver, sinusoidal perfusion failure, as well as the transaminase activities were strongly increased on I/R as compared with the sham-operated mice. Inhibition of the RIP1-dependent pathway with Nec-1, however, did not attenuate I/R-induced leukocyte migration, perfusion failure, and hepatocellular injury. Western blot analysis showed a baseline RIP1 expression in livers from sham-operated mice, whereas RIP1 expression was not detectable in both Nec-1-treated and vehicle-treated I/R group. Caspase-3 activity was significantly elevated after I/R in both postischemic groups. Our in vivo data show that RIP1-mediated necroptosis is not present in the postischemic liver and that I/R-induced caspase activation is associated with loss of RIP1 expression. Because caspases are able to cleave RIP1, we hypothesize that I/R-triggered caspase activation negatively regulates necroptosis and, thereby, determines apoptosis as a preferred route of cell death after hepatic I/R.

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Section: Discussionmentioning

confidence: 98%

RIP1-Dependent Programmed Necrosis is Negatively Regulated by Caspases During Hepatic Ischemia-Reperfusion

Rosentreter

Funken²,

Reifart³

et al. 2015

Shock

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“…Further evidence for indirect control of cell growth and repair comes from another study involving conditional caspase-8 knockout mice. Mice with hepatocyte-specific deletion of caspase-8 (Casp8 Δhepa ) show greatly improved liver regeneration due to increased NFκB signaling 113 and wound healing. Caspase-7 has another important role in osteogenesis.…”

Section: Caspases In Cell Proliferation and Tissue Regenerationmentioning

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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“…Hepatocyte-specific caspase-8 and NEMO double-knockout mice showed massive liver necrosis and cholestasis [62]. Caspase-8 deletion inhibited proteolytic cleavage of RIP1, resulting in the formation of FADD-RIP1–RIP3 kinase complexes required for the programmed necrosis and premature activation of NF-κB and JNK [62, 63]. RIP3 is overexpressed in the livers of human NASH patients and MCD diet-fed mice [64].…”

Section: Tnfα Signaling In Liver Fibrosismentioning

confidence: 99%

TNFα in Liver Fibrosis

2015

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Hepatocyte death, inflammation, and liver fibrosis are the hallmarks of chronic liver disease. Tumor necrosis factor-α (TNFα) is an inflammatory cytokine involved in liver inflammation and sustained liver inflammation leads to liver fibrosis. TNFα exerts inflammation, proliferation, and apoptosis. However, the role of TNFα signaling in liver fibrosis is not fully understood. This review highlights the recent findings demonstrating the molecular mechanisms of TNFα and its downstream signaling in liver fibrosis. During the progression of liver fibrosis, hepatic stellate cells play a pivotal role in a dynamic process of production of extracellular matrix proteins and modulation of immune response. Hepatic stellate cells transdifferentiate into activated myofibroblasts in response to damaged hepatocyte-derived mediators and immune cell-derived cytokines/chemokines. Here, we will discuss the role of TNFα in hepatic stellate cell survival and activation and the crosstalk between hepatic stellate cells and hepatocytes or other immune cells, such as macrophages, dendritic cells, and B cells in the development of liver fibrosis.

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Loss of caspase-8 in hepatocytes accelerates the onset of liver regeneration in mice through premature nuclear factor kappa B activation

Cited by 30 publications

References 27 publications

RIP1-Dependent Programmed Necrosis is Negatively Regulated by Caspases During Hepatic Ischemia-Reperfusion

RIP1-Dependent Programmed Necrosis is Negatively Regulated by Caspases During Hepatic Ischemia-Reperfusion

Old, new and emerging functions of caspases

TNFα in Liver Fibrosis

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