Molecular dissection of gp130-dependent pathways in hepatocytes during liver regeneration.
Interleukin-6 (IL-6) via its signal transducer gp130 is an important mediator of liver regeneration involved in protecting from lipopolysaccharide (LPS)-induced liver injury after partial hepatectomy (PH). Here we generated mice either defective (Delta) in hepatocyte-specific gp130-dependent Ras or STAT activation to define their role during liver regeneration. Deletion of gp130-dependent signaling had major impact on acute phase gene (APG) regulation after PH. APG expression was blocked in gp130-DeltaSTAT animals, whereas gp130-DeltaRas mice showed an enhanced APG response and stronger SOCS3 regulation correlating with delayed hepatocyte proliferation. To define the role of SOCS3 during hepatocyte proliferation, primary hepatocytes were co-stimulated with IL-6 and hepatocyte growth factor. Higher SOCS3 expression in gp130-DeltaRas hepatocytes correlated with delayed hepatocyte proliferation. Next, we tested the impact of LPS, mimicking bacterial infection, on liver regeneration. LPS and PH induced SOCS3 and APG in all animal strains and delayed cell cycle progression. Additionally, IL-6/gp130-dependent STAT3 activation in hepatocytes was essential in mediating protection and thus required for maximal proliferation. Unexpectedly, oncostatin M was most strongly induced in gp130-DeltaSTAT animals after PH/LPS-induced stress and was associated with hepatocyte proliferation in this strain. In summary, gp130-dependent STAT3 activation and concomitant SOCS3 during liver regeneration is involved in timing of DNA synthesis and protects hepatocyte proliferation during stress conditions.
Dierssen
Uta
U
Internal Medicine III, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen, Pauwelsstrasse 30, Aachen, Germany.
Beraza
Naiara
N
Lutz
Holger H
HH
Liedtke
Christian
C
Ernst
Matthias
M
Wasmuth
Hermann E
HE
Trautwein
Christian
C
D000210:Acute-Phase Reaction / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001424:Bacterial Infections / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D005260:Female; D006498:Hepatectomy; D022781:Hepatocytes / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000293:injuries / Q000378:metabolism*; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
C494200:Il6st protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050822:Cytokine Receptor gp130; D004247:DNA; D016283:Proto-Oncogene Proteins p21(ras)