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J. Biol. Chem., Vol. 283, Issue 15, 9886-9895, April 11, 2008

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Molecular Dissection of gp130-dependent Pathways in Hepatocytes during Liver Regeneration^*

Uta Dierssen, Naiara Beraza, Holger H. Lutz, Christian Liedtke, Matthias Ernst, Hermann E. Wasmuth, and Christian Trautwein¹

From the Internal Medicine III, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen, Germany and the Colon Molecular and Cell Biology Laboratory, Ludwig Institute for Cancer Research, Parkville, Victoria 3050, Australia

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 () 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-STAT animals, whereas gp130-Ras 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-Ras 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-STAT 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.

Received for publication, July 5, 2007 , and in revised form, November 21, 2007.

^* This work was supported by the Sonderforschungsbereich 542, Teilprojekt, C14. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Medizinische Klinik III, University Hospital, RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany. Tel.: 49-241-80-80-860; Fax: 49-241-80-82-455; E-mail: ctrautwein{at}ukaachen.de.

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