Early hepatocyte DNA synthetic response posthepatectomy is modulated by IL-6 trans-signaling and PI3K/AKT activation
| Autor: | Yael Nechemia-Arbely, Orit Pappo, Ulrich Denz, Stefan Rose-John, Eithan Galun, Jonathan H. Axelrod, Claudia Drucker, Jürgen Scheller, Jonathan Raub, Anat Shriki |
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| Rok vydání: | 2011 |
| Předmět: |
Male
STAT3 Transcription Factor Gene Expression Mitosis Biology Transfection Mice Phosphatidylinositol 3-Kinases medicine Animals Hepatectomy Protein kinase B PI3K/AKT/mTOR pathway Mice Inbred BALB C Hepatology Interleukin-6 Cell cycle Receptors Interleukin-6 Liver regeneration Liver Regeneration Cell biology Mice Inbred C57BL medicine.anatomical_structure Biochemistry Hepatocyte Hepatocytes Ectopic expression Hepatocyte growth factor Mitogen-Activated Protein Kinases Signal transduction Proto-Oncogene Proteins c-akt Signal Transduction medicine.drug |
| Zdroj: | Journal of Hepatology. 54:922-929 |
| ISSN: | 0168-8278 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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