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

Hepatology. 2004 May;39(5):1332-42. doi: 10.1002/hep.20184.

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.

MeSH terms

  • Agar
  • Animals
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / pathology
  • Cell Division / physiology
  • Cell Line, Tumor
  • Cell Survival / immunology
  • Chemical and Drug Induced Liver Injury / immunology
  • Chemical and Drug Induced Liver Injury / physiopathology
  • Concanavalin A
  • DNA-Binding Proteins / metabolism*
  • Hepatitis / immunology*
  • Hepatitis / physiopathology
  • Hepatocytes / cytology
  • Hepatocytes / immunology
  • Hepatocytes / metabolism
  • Humans
  • Interleukins / genetics
  • Interleukins / immunology*
  • Interleukins / metabolism
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / metabolism
  • STAT3 Transcription Factor
  • T-Lymphocytes / immunology*
  • Trans-Activators / metabolism*

Substances

  • DNA-Binding Proteins
  • Interleukins
  • Receptors, Interleukin
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Trans-Activators
  • interleukin-22 receptor
  • Concanavalin A
  • Agar
  • interleukin-22