title: Early hepatocyte DNA synthetic response posthepatectomy is modulated by IL-6 trans-signaling and PI3K/AKT activation.
abstract: OBJECTIVE
  Interleukin-6 (IL-6) is a crucial factor in liver regeneration following partial hepatectomy (PH); however, the role of IL-6 and IL-6 trans-signaling in particular, in hepatocyte mitosis remains controversial. IL-6 trans-signaling relies upon the release of the soluble IL-6R (sIL-6R), which binds IL-6 to form an agonistic IL-6/sIL-6R complex. Herein we have examined the hypothesis that IL-6 trans-signaling plays a crucial and distinct role in liver regeneration following PH.
  
  
  METHODS
  The specific IL-6/sIL-6R antagonist, sgp130Fc, was expressed in mice and analyzed for its effect on hepatocyte mitosis following PH. Alternatively, we examined the effect of the IL-6/sIL-6R super-agonist, Hyper-IL-6, or IL-6 expressed either alone or in combination with hepatocyte growth factor (HGF) on hepatocyte mitosis in the absence of PH.
  
  
  RESULTS
  Following PH, the dramatic rise of circulating IL-6 levels is accompanied by a concurrent ∼2-fold increase in circulating sIL-6R levels. Ectopic expression of sgp130Fc reduced hepatocyte mitosis by about 40% at early times following PH, while substantially reducing AKT, but not STAT3, activation. But, ectopic Hyper-IL-6 expression in mice without PH was not mitogenic to hepatocytes in vivo. Rather, Hyper-IL-6, but not IL-6, markedly increased HGF-induced hepatocyte mitosis. This cooperative effect correlated with greater resistance of HIL-6 than IL-6 to HGF-mediated reduction of AKT activation, rather than changes in STAT3 or MAPK signaling, and was completely blocked by PI3K inhibition.
  
  
  CONCLUSIONS
  Following PH, IL-6/sIL-6R cooperates with growth factors, through a PI3K/AKT-dependent mechanism to promote entry of hepatocytes into the cell cycle.
authors.affiliation: The Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Nechemia-Arbely
authors.forename: Anat
authors.initials: A
authors.lastname: Shriki
authors.forename: Ulrich
authors.initials: U
authors.lastname: Denz
authors.forename: Claudia
authors.initials: C
authors.lastname: Drucker
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.forename: Jonathan
authors.initials: J
authors.lastname: Raub
authors.forename: Orit
authors.initials: O
authors.lastname: Pappo
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Eithan
authors.initials: E
authors.lastname: Galun
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Axelrod
mesh_terms: D000818:Animals; D015870:Gene Expression / Q000502:physiology; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000502:physiology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008938:Mitosis / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases