Early hepatocyte DNA synthetic response posthepatectomy is modulated by IL-6 trans-signaling and PI3K/AKT activation

Yael Nechemia-Arbely, Anat Shriki, Ulrich Denz, Claudia Drucker, Jürgen Scheller, Jonathan Raub, Orit Pappo, Stefan Rose-John, Eithan Galun, Jonathan H. Axelrod

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Background & Aims: 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.

Original languageAmerican English
Pages (from-to)922-929
Number of pages8
JournalJournal of Hepatology
Issue number5
StatePublished - May 2011
Externally publishedYes

Bibliographical note

Funding Information:
These studies were supported by grants from the Israel Science Foundation (Jerusalem, Israel) (ISF 614/01 and ISF 853/04) to JHA and EG, and by grants from the Deutsche Forschungsgemeinschaft (RO632/13-1) and SFB415 to SRJ and to JS (SFB415).


  • HIL-6
  • IL-6
  • IL-6 trans-signaling
  • Liver regeneration
  • PI3K/AKT
  • sIL-6R
  • sgp130


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