A key pathogenic role for the STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation

Hepatology. 2003 Dec;38(6):1573-80. doi: 10.1016/j.hep.2003.09.020.

Abstract

TH1 cytokines have been suggested to contribute to the pathogenesis of T-cell-mediated liver injury and inflammation. However, the molecular signaling pathways involved in such injury are still poorly understood. In the present study, we investigated the role of the STAT1/T-bet signaling pathway in a murine model of T-cell-mediated liver inflammation induced by the application of concanavalin A (Con A) using newly created STAT1 transgenic mice as well as STAT1- and T-bet-deficient mice. Liver injury induced by Con A was associated with an increase of both pSTAT1 and T-bet levels in the liver. Furthermore, functional studies suggested a pathogenic role for STAT1 in Con A-induced liver injury, because transgenic mice overexpressing STAT1 under the control of the CD2 promoter/enhancer construct showed elevated interferon gamma (IFN-gamma) and IRF-1 levels as well as significantly augmented liver injury following administration of Con A. Consistently, we observed that both STAT1-deficient and T-bet-deficient mice were protected from such T-cell-dependent liver injury. In conclusion, these findings suggest a key pathogenic role for the STAT1/T-bet signaling pathway for T-cell activation in the Con A model of T-cell-mediated liver pathology.

MeSH terms

  • Animals
  • Concanavalin A / toxicity
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / physiology*
  • Hepatitis / etiology*
  • Interferon Regulatory Factor-1
  • Interferon-gamma / biosynthesis
  • Liver / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phosphoproteins / biosynthesis
  • STAT1 Transcription Factor
  • Signal Transduction / physiology*
  • T-Box Domain Proteins
  • T-Lymphocytes / immunology*
  • Trans-Activators / physiology*
  • Transcription Factors / physiology*

Substances

  • DNA-Binding Proteins
  • Interferon Regulatory Factor-1
  • Irf1 protein, mouse
  • Phosphoproteins
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Trans-Activators
  • Transcription Factors
  • Concanavalin A
  • Interferon-gamma