title: Interleukin-1 receptor antagonist modulates the early phase of liver regeneration after partial hepatectomy in mice.
abstract: BACKGROUND
  Cytokine administration is a potential therapy for acute liver failure by reducing inflammatory responses and favour hepatocyte regeneration. The aim of this study was to evaluate the role of interleukin-1 receptor antagonist (IL-1ra) during liver regeneration and to study the effect of a recombinant human IL-1ra on liver regeneration.
  
  
  METHODS
  We performed 70%-hepatectomy in wild type (WT) mice, IL-1ra knock-out (KO) mice and in WT mice treated by anakinra. We analyzed liver regeneration at regular intervals by measuring the blood levels of cytokines, the hepatocyte proliferation by bromodeoxyuridin (BrdU) incorporation, proliferating cell nuclear antigen (PCNA) and Cyclin D1 expression. The effect of anakinra on hepatocyte proliferation was also tested in vitro using human hepatocytes.
  
  
  RESULTS
  At 24h and at 48 h after hepatectomy, IL-1ra KO mice had significantly higher levels of pro-inflammatory cytokines (IL-6, IL-1β and MCP-1) and a reduced and delayed hepatocyte proliferation measured by BrdU incorporation, PCNA and Cyclin D1 protein levels, when compared to WT mice. IGFBP-1 and C/EBPβ expression was significantly decreased in IL-1ra KO compared to WT mice. WT mice treated with anakinra showed significantly decreased levels of IL-6 and significantly higher hepatocyte proliferation at 24h compared to untreated WT mice. In vitro, primary human hepatocytes treated with anakinra showed significantly higher proliferation at 24h compared to hepatocytes without treatment.
  
  
  CONCLUSIONS
  IL1ra modulates the early phase of liver regeneration by decreasing the inflammatory stress and accelerating the entry of hepatocytes in proliferation. IL1ra might be a therapeutic target to improve hepatocyte proliferation.
authors: Surgical Research Unit, Department of Surgery, Geneva University Hospital and University of Geneva, Geneva, Switzerland.
authors: Antonino
authors: A
authors: Sgroi
authors: Carmen
authors: C
authors: Gonelle-Gispert
authors: Philippe
authors: P
authors: Morel
authors: Reto Marc
authors: RM
authors: Baertschiger
authors: Nadja
authors: N
authors: Niclauss
authors: Gilles
authors: G
authors: Mentha
authors: Pietro
authors: P
authors: Majno
authors: Veronique
authors: V
authors: Serre-Beinier
authors: Leo
authors: L
authors: Buhler
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D055786:Gene Knockout Techniques; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008115:Liver Regeneration / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D013997:Time Factors
chemical_list: D018797:Cell Cycle Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D000410:Alanine Transaminase