title: Loss of caspase-8 in hepatocytes accelerates the onset of liver regeneration in mice through premature nuclear factor kappa B activation.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine III, University Hospital Aachen, Aachen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Freimuth
authors.forename: Jörg-Martin
authors.initials: JM
authors.lastname: Bangen
authors.forename: Daniela
authors.initials: D
authors.lastname: Lambertz
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Yulia Alexandrowna
authors.initials: YA
authors.lastname: Nevzorova
authors.forename: Roland
authors.initials: R
authors.lastname: Sonntag
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.forename: Dieter
authors.initials: D
authors.lastname: Riethmacher
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Christian
authors.initials: C
authors.lastname: Liedtke
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000502:physiology*; D002779:Cholestasis / Q000209:etiology; D020690:GTPase-Activating Proteins / Q000502:physiology; D022781:Hepatocytes / Q000201:enzymology*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D008099:Liver / Q000473:pathology; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D009336:Necrosis; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; C490620:Ralbp1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D053181:Caspase 8