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Am J Physiol Gastrointest Liver Physiol 292: G1019-G1028, 2007. First published January 4, 2007; doi:10.1152/ajpgi.00239.2006
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LIVER AND BILIARY TRACT

IL-22-mediated liver cell regeneration is abrogated by SOCS-1/3 overexpression in vitro

Stephan Brand,1,* Julia Dambacher,1,* Florian Beigel,1 Kathrin Zitzmann,1 Malte H. J. Heeg,1 Thomas S. Weiss,3 Thomas Prüfer,1 Torsten Olszak,1 Christian J. Steib,1 Martin Storr,1 Burkhard Göke,1 Helmut Diepolder,1 Manfred Bilzer,1 Wolfgang E. Thasler,2 and Christoph J. Auernhammer1

1Department of Medicine II and 2Department of Surgery, University-Hospital Munich-Grosshadern and University of Munich, Munich; and 3Center for Liver Cell Research, University Hospital Regensburg, Regensburg, Germany

Submitted 1 June 2006 ; accepted in final form 20 December 2006

The IL-10-like cytokine IL-22 is produced by activated T cells. In this study, we analyzed the role of this cytokine system in hepatic cells. Expression studies were performed by RT-PCR and quantitative PCR. Signal transduction was analyzed by Western blot experiments and ELISA. Cell proliferation was measured by MTS and [3H]thymidine incorporation assays. Hepatocyte regeneration was studied in in vitro restitution assays. Binding of IL-22 to its receptor complex expressed on human hepatic cells and primary human hepatocytes resulted in the activation of MAPKs, Akt, and STAT proteins. IL-22 stimulated cell proliferation and migration, which were both significantly inhibited by the phosphatidylinositol 3-kinase inhibitor wortmannin. IL-22 increased the mRNA expression of suppressor of cytokine signaling (SOCS)-3 and the proinflammatory cytokines IL-6, IL-8, and TNF-{alpha}. SOCS-1/3 overexpression abrogated IL-22-induced STAT activation and decreased IL-22-mediated liver cell regeneration. Hepatic IL-22 mRNA expression was detectable in different forms of human hepatitis, and hepatic IL-22 mRNA levels were increased in murine T cell-mediated hepatitis in vivo following cytomegalovirus infection, whereas no significant differences were seen in an in vivo model of ischemia-reperfusion injury. In conclusion, IL-22 promotes liver cell regeneration by increasing hepatic cell proliferation and hepatocyte migration through the activation of Akt and STAT signaling, which is abrogated by SOCS-1/3 overexpression.

interleukin-10-like cytokines; liver regeneration; cell migration; suppressor of cytokine signaling


Address for reprint requests and other correspondence: S. Brand, Dept. of Medicine II, Univ.-Hospital Munich-Grosshadern and Univ. of Munich, Marchioninistrasse 15, 81377 Munich, Germany (e-mail: stephan.brand{at}med.uni-muenchen.de)






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