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

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 [H-3] 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.