Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS

J Clin Invest. 2002 Nov;110(10):1503-13. doi: 10.1172/JCI15841.

Abstract

T cell-mediated fulminant hepatitis is a life-threatening event for which the underlying mechanism is not fully understood. Injection of concanavalin A (Con A) into mice recapitulates the histological and pathological sequelae of T cell-mediated hepatitis. In this model, both signal transducer and activator of transcription factor 1 (STAT1) and STAT3 are activated in the liver. Disruption of the STAT1 gene by way of genetic knockout attenuates liver injury, suppresses CD4(+) and NK T cell activation, and downregulates expression of proapoptotic interferon regulatory factor-1 protein and suppressor of cytokine signaling-1 (SOCS1), but enhances STAT3 activation and STAT3-controlled antiapoptotic signals. Studies from IFN-gamma-deficient mice indicate that IFN-gamma not only is the major cytokine responsible for STAT1 activation but also partially accounts for STAT3 activation. Moreover, downregulation of STAT3 activation in IL-6-deficient mice is associated with decreased STAT3-controlled antiapoptotic signals and expression of SOCS3, but upregulation of STAT1 activation and STAT1-induced proapoptotic signals and exacerbation of liver injury. Taken together, these findings suggest that STAT1 plays a harmful role in Con A-mediated hepatitis by activation of CD4(+) and NK T cells and directly inducing hepatocyte death, whereas STAT3 protects against liver injury by suppression of IFN-gamma signaling and induction of antiapoptotic protein Bcl-X(L). STAT1 and STAT3 in hepatocytes also negatively regulate one another through the induction of SOCS.

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Concanavalin A / toxicity
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Hepatitis, Autoimmune / etiology
  • Hepatitis, Autoimmune / immunology
  • Hepatitis, Autoimmune / metabolism*
  • Hepatitis, Autoimmune / pathology
  • Humans
  • Interferon-gamma / deficiency
  • Interferon-gamma / genetics
  • Interleukin-6 / deficiency
  • Interleukin-6 / genetics
  • Intracellular Signaling Peptides and Proteins*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Repressor Proteins*
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Signal Transduction
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • T-Lymphocytes / immunology*
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors*

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • Proteins
  • RNA, Messenger
  • Repressor Proteins
  • SOCS1 protein, human
  • SOCS3 protein, human
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Socs1 protein, mouse
  • Socs3 protein, mouse
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Transcription Factors
  • Concanavalin A
  • Interferon-gamma