Background/Aims: The interleukin (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. Methods: 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. Results: Binding of IL-22 to its receptor complex expressed on human hepatic cells and primary human hepatocytes results in activation of MAP kinases, Akt and STAT proteins. IL-22 stimulates cell proliferation and migration which are both significantly inhibited by the PI3 kinase inhibitor wortmannin. IL-22 increases mRNA expression of SOCS-3 and the proinflammatory cytokines IL-6, IL-8, and TNF-. SOCS-1/3 overexpression abrogates IL-22 induced STAT activation and decreases 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 while no significant differences were seen in an in vivo model of ischemia reperfusion injury. Conclusions: IL-22 promotes liver cell regeneration by increasing hepatic cell proliferation and hepatocyte migration through activation of Akt and STAT signaling which is abrogated by SOCS-1/3 overexpression.