title: Hepatocyte-specific inhibitor-of-kappaB-kinase deletion triggers the innate immune response and promotes earlier cell proliferation during liver regeneration.
abstract: Nuclear factor kappaB (NF-kappaB) is one of the main transcription factors involved in liver regeneration after partial hepatectomy (PH). It is activated upon IkappaB phosphorylation by the IkappaB kinase (IKK) complex comprising inhibitor of kappaB kinase 1 (IKK1), inhibitor of kappaB kinase 2 (IKK2), and nuclear factor-B essential modifier (NEMO). We studied the impact of hepatocyte-specific IKK2 deletion during liver regeneration. A 70% PH was performed on IKK2(f/f) (wild-type) and IKK2DeltaLPCmice (hepatocyte-specific IKK2 knockout mice). PH in IKK2DeltaLPC compared with IKK2(f/f) mice resulted in weaker and delayed NF-kappaB activation in hepatocytes, while nonparenchymal liver cells showed earlier NF-kappaB activation and higher tumor necrosis factor expression. Additionally, these animals showed increased and earlier serum amyloid A and chemotactic cytokine L-1 levels followed by enhanced polymorphonuclear cell recruitment to the liver. These results correlated with earlier Jun kinase activity, c-myc expression, and matrix metalloproteinase-9 activity, suggesting earlier priming in IKK2DeltaLPC mice after PH. These data preceded a more rapid cell cycle progression and earlier hepatocyte proliferation as evidenced through cyclin and 5-bromo-2-deoxyuridine analysis. Interestingly, despite faster G(1)/S progression, IKK2DeltaLPC mice exhibited an enduring mitosis phase, because mitotic bodies were still observed at later stages after PH.
  
  
  CONCLUSIONS
  We demonstrate that PH in IKK2DeltaLPC mice triggers a more rapid and pronounced inflammatory response in nonparenchymal liver cells, which triggers earlier hepatocyte proliferation.
authors.affiliation: Medical Clinic III, University Hospital Aachen (RWTH), Aachen, Germany.
authors.forename: Yann
authors.initials: Y
authors.lastname: Malato
authors.forename: Leif E
authors.initials: LE
authors.lastname: Sander
authors.forename: Christian
authors.initials: C
authors.lastname: Liedtke
authors.forename: Malika
authors.initials: M
authors.lastname: Al-Masaoudi
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Naiara
authors.initials: N
authors.lastname: Beraza
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D054360:Chemokine CXCL1 / Q000378:metabolism; D017353:Gene Deletion; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000235:genetics* / Q000378:metabolism*; D007113:Immunity, Innate / Q000235:genetics* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008115:Liver Regeneration / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D016196:S Phase / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse