Abstract
Abstract
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-α. 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.
the liver has great regenerative potential (10), and liver regeneration following partial hepatectomy is controlled by a complex interplay of cytokines and growth factors (21). Two known regulators of the priming phase of liver regeneration are the cytokines TNF-α and IL-6 (14, 63), which are increasingly expressed after partial hepatectomy (54, 63). In mice lacking either IL-6 or TNF receptor 1 (p55/TNFR1), liver cell regeneration is impaired after partial hepatectomy (14, 63), which can be restored by a preoperative injection of IL-6 (14). Detailed analysis of IL-6 signaling identified STAT phosphorylation as an essential pathway involved in liver cell regeneration (26). It has been demonstrated that STAT3 is activated after partial hepatectomy as the result of increased IL-6 levels (14, 63), implicating both IL-6 and STAT3 as part of the priming mechanism for hepatocyte proliferation. Moreover, TNF-α and IL-6, the two key cytokines involved in liver cell regeneration, induce suppressor of cytokine signaling (SOCS)-3 mRNA, which is also induced by partial hepatectomy (12). Recently, we (5) demonstrated STAT activation and induction of SOCS-3 mRNA by IL-22, a novel IL-10-related cytokine, in intestinal epithelial cells. Given its STAT-inducing capacity, we hypothesized a role for this cytokine in liver cell regeneration that is also supported by the protective effects of IL-22 in a murine model of chemically induced hepatitis (46).
IL-22 was originally called IL-10-related T cell-derived inducible factor (IL-TIF) and was described as an IL-9-inducible gene (19). The IL-22 receptor (IL-22R) complex consists of two subunits, IL-22R1 and IL-10R2, which both belong to the class II cytokine receptor family (34). Upon binding to its R1 chain, IL-22 induces a conformational change that enables IL-10R2 to interact with the newly formed ligand-receptor complexes. This, in turn, activates a signal transduction cascade that results in the rapid activation of several transcription factors, including STAT proteins (3, 19, 37).
IL-22Rs are expressed on a variety of tissues, including the kidney, pancreas, and liver (34). Major sources of IL-22 are activated T and natural killer cells (60). As known so far, IL-22 seems to play a role in inflammatory processes, e.g., through upregulation of acute-phase reactants in the liver and hepatoma cells (19).
Although expression of the IL-22R complex has been demonstrated in hepatoma cell lines (37), comprehensive analyses of its expression in hepatic cell lines, including primary human hepatocytes, and of its detailed signal transduction, including its specific functions in hepatocyte regeneration, have not been performed yet. Therefore, elucidating these roles of IL-22 were the aims of this study. In addition, we analyzed the role of SOCS proteins in IL-22-mediated functions and signaling pathways.
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