title: 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.
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.
authors.affiliation: Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Radaeva
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.forename: Hong-Na
authors.initials: HN
authors.lastname: Pan
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
mesh_terms: D000362:Agar; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000503:physiopathology; D003208:Concanavalin A; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006505:Hepatitis / Q000276:immunology* / Q000503:physiopathology; D022781:Hepatocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism*; D000097043:Interleukin-22
chemical_list: D000362:Agar; D003208:Concanavalin A; D004268:DNA-Binding Proteins; D007378:Interleukins; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D000097043:Interleukin-22; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C415369:interleukin-22 receptor