title: Hepatitis B virus HBx protein impairs liver regeneration through enhanced expression of IL-6 in transgenic mice.
abstract: OBJECTIVE
  Conflicting results have been reported regarding the impact of hepatitis B virus X protein (HBx) expression on liver regeneration triggered by partial hepatectomy (PH). In the present report we investigated the mechanisms by which HBx protein alters hepatocyte proliferation after PH.
  
  
  METHODS
  PH was performed on a transgenic mouse model in which HBx expression is under the control of viral regulatory elements and liver regeneration was monitored. LPS, IL-6 neutralizing antibody, and SB203580 were injected after PH to evaluate IL-6 participation during liver regeneration.
  
  
  RESULTS
  Cell cycle progression of hepatocytes was delayed in HBx transgenic mice compared to WT animals. Moreover, HBx induced higher secretion of IL-6 soon after PH. Upregulation of IL-6 was associated with an elevation of STAT3 phosphorylation, SOCS3 transcript accumulation and a decrease in ERK1/2 phosphorylation in the livers of HBx transgenic mice. The involvement of IL-6 overexpression in cell cycle deregulation was confirmed by the inhibition of liver regeneration in control mice after the upregulation of IL-6 expression using LPS. In addition, IL-6 neutralization with antibodies was able to restore liver regeneration in HBx mice. Finally, the direct role of p38 in IL-6 secretion after PH was demonstrated using SB203580, a pharmacological inhibitor.
  
  
  CONCLUSIONS
  HBx is able to induce delayed hepatocyte proliferation after PH, and HBx-induced IL-6 overexpression is involved in delayed liver regeneration. By modulating IL-6 expression during liver proliferation induced by stimulation of the cellular microenvironment, HBx may participate in cell cycle deregulation and progression of liver disease.
authors.affiliation: Inserm, U845, Pathogenèse des hépatites virales B et immunothérapie, Paris, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Quétier
authors.forename: Nicolas
authors.initials: N
authors.lastname: Brezillon
authors.forename: Marion
authors.initials: M
authors.lastname: Duriez
authors.forename: Hélène
authors.initials: H
authors.lastname: Massinet
authors.forename: Eric
authors.initials: E
authors.lastname: Giang
authors.forename: James
authors.initials: J
authors.lastname: Ahodantin
authors.forename: Céline
authors.initials: C
authors.lastname: Lamant
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Brunelle
authors.forename: Patrick
authors.initials: P
authors.lastname: Soussan
authors.forename: Dina
authors.initials: D
authors.lastname: Kremsdorf
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D002453:Cell Cycle; D049109:Cell Proliferation; D004742:Enhancer Elements, Genetic; D006498:Hepatectomy; D006515:Hepatitis B virus / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000473:pathology / Q000821:virology; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D015850:Interleukin-6 / Q000502:physiology*; D008115:Liver Regeneration / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000008:administration & dosage; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins; D000093242:Interleukin-6 Inhibitors
chemical_list: D057134:Antibodies, Neutralizing; D007093:Imidazoles; D015850:Interleukin-6; D011725:Pyridines; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D000093242:Interleukin-6 Inhibitors; C057628:hepatitis B virus X protein; C093642:SB 203580
keywords: HBV; HBx; HCC; PH; hepatitis B virus; hepatitis B virus X protein; hepatocellular carcinoma; partial hepatectomy