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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
Author(s) -
Freimuth Julia,
Bangen JörgMartin,
Lambertz Daniela,
Hu Wei,
Nevzorova Yulia Alexandrowna,
Sonntag Roland,
Gassler Nikolaus,
Riethmacher Dieter,
Trautwein Christian,
Liedtke Christian
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26538
Subject(s) - liver regeneration , microbiology and biotechnology , regeneration (biology) , tumor necrosis factor alpha , hepatocyte , biology , tumor necrosis factor receptor 1 , kinase , signal transduction , apoptosis , cancer research , chemistry , immunology , biochemistry , in vitro , tumor necrosis factor receptor
The cytokine tumor necrosis factor alpha (TNF‐α; TNF) plays a critical role early in liver regeneration following partial hepatectomy (PH). TNF stimulates at least three different pathways leading to nuclear factor kappa B (NF‐κB) activation, apoptosis signaling by way of caspase‐8 (Casp8), and activation of cJun N‐terminal kinases (JNK). The present study aimed to better define the role of Casp8 during liver regeneration. We performed PH in mice lacking Casp8 specifically in hepatocytes (Casp8 Δhepa ) and determined their liver regeneration capacity by measuring liver mass restoration and kinetics of cell cycle progression. Casp8 Δhepa mice showed an accelerated onset of DNA synthesis after PH, delayed hepatocyte mitosis, but overall normal liver mass restoration. Analysis of immediate TNF‐dependent signaling pathways revealed that loss of Casp8 prevents proteolytic cleavage of the receptor‐interacting protein 1 (RIP1) in hepatocytes and subsequently triggers premature activation of NF‐κB and JNK/cJun related signals. In order to define the role of NF‐κB in this setting we blocked NF‐κB activation in Casp8 Δhepa mice by concomitant inactivation of the NF‐κB essential modulator (NEMO) in hepatocytes. Lack of NEMO largely reverted aberrant DNA synthesis in Casp8 Δhepa mice but resulted in incomplete termination of the regeneration process and hepatomegaly. Conclusion : Casp8 comprises a nonapoptotic function during liver regeneration by balancing RIP1, NF‐κB, and JNK activation. While loss of Casp8 triggers NF‐κB activation and thus improves liver regeneration, combined loss of Casp8 and NEMO impairs a controlled regenerative response and drives hepatomegaly. (H epatology 2013;58:1779–1789)