Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation

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Abstract

The central role of T cell activation in hepatocellular injury has been well documented. In this article, we provide evidence suggesting that T cells may also play a protective role in liver disease by releasing interleukin-22 (IL-22), a recently identified T cell-derived cytokine whose biological significance is unclear. IL-22 messenger RNA and protein expression are significantly elevated in T cell-mediated hepatitis induced by concanavalin A (ConA) but are less extensively elevated in the carbon tetrachloride-induced liver injury model. Activated CD3(+) T cells are likely responsible for the production of IL-22 in the liver after injection of ConA. The IL-22 receptor is normally expressed at high levels by hepatocytes and further induced after ConA injection. IL-22 blockade with a neutralizing antibody reduces signal transducer and activator of transcription factor 3 (STAT3) activation and worsens liver injury in T cell-mediated hepatitis, whereas injection of recombinant IL-22 attenuates such injury. In vitro treatment with recombinant IL-22 or overexpression of IL-22 promotes cell growth and survival in human hepatocellular carcinoma HepG2 cells. Stable overexpression of IL-22 in HepG2 cells constitutively activates STAT3 and induces expression of a variety of antiapoptotic (e.g., Bcl-2, Bcl-xL, Mcl-1) and mitogenic (e.g., c-myc, cyclin D1, Rb2, CDK4) proteins. Blocking STAT3 activation abolishes the antiapoptotic and mitogenic actions of IL-22 in hepatic cells. In conclusion, the T cell-derived cytokine IL-22 is a survival factor for hepatocytes; this suggests that T cell activation may also prevent and repair liver injury by releasing hepatoprotective cytokine IL-22 in addition to its previously documented central role in hepatocellular injury.

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