Dissection of the intracellular pathways in hepatocytes suggests a role for Jun kinase and IFN regulatory factor-1 in Con A-induced liver failure

J Immunol. 2001 Jul 1;167(1):514-23. doi: 10.4049/jimmunol.167.1.514.

Abstract

Con A administration results in dose-dependent immune-mediated liver injury. Cytokines are important to determine the outcome of liver failure in this model, and especially TNF-alpha and IFN-gamma directly contribute to hepatocyte damage. The intracellular pathways of these two cytokines, which eventually result in tissue destruction, are not well defined. Here we used anti-IFN-gamma Abs and adenoviral vectors that express molecules inhibiting distinct TNF-alpha-dependent pathways in hepatocytes to better understand the relevance of specific intracellular signaling cascades for Con A-induced liver failure. We show that activation of TNF-alpha- and IFN-gamma-dependent intracellular pathways occurs prior to the influx of immune-activated cells into the liver and that anti-TNF-alpha and anti-IFN-gamma neutralizing Abs cannot block infiltration of these cells. Blocking experiments with Abs and adenoviral vectors showed that NF-kappaB activation and the Fas-associated death domain protein/caspase 8 cascade in hepatocytes during Con A-induced liver failure have no impact on tissue injury. Additionally, STAT1 activation alone after Con A injection in liver cells does not result in liver damage. In contrast, IFN-gamma-dependent expression of IFN regulatory factor-1 and TNF-alpha-dependent activation of c-Jun N-terminal kinase in liver cells correlates with liver cell damage after Con A injection. Therefore, our experiments indicate that 11418690

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • CD4-Positive T-Lymphocytes / pathology
  • Carrier Proteins / metabolism
  • Cell Movement / immunology
  • Concanavalin A / administration & dosage*
  • Concanavalin A / pharmacology
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Fas-Associated Death Domain Protein
  • Hepatocytes / enzymology*
  • Hepatocytes / immunology
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Immune Sera / administration & dosage
  • Injections, Intravenous
  • Interferon Regulatory Factor-1
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / immunology
  • Interferon-gamma / physiology*
  • Intracellular Fluid / enzymology*
  • Intracellular Fluid / immunology
  • JNK Mitogen-Activated Protein Kinases
  • Leukocyte Common Antigens / biosynthesis
  • Liver Failure / enzymology*
  • Liver Failure / immunology*
  • Liver Failure / pathology
  • Liver Failure / prevention & control
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinases / physiology*
  • NF-kappa B / metabolism
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / metabolism
  • Phosphoproteins / physiology*
  • STAT1 Transcription Factor
  • Signal Transduction / immunology
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / metabolism
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology
  • fas Receptor / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA-Binding Proteins
  • FADD protein, human
  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • IRF1 protein, human
  • Immune Sera
  • Interferon Regulatory Factor-1
  • Irf1 protein, mouse
  • NF-kappa B
  • Phosphoproteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Stat1 protein, mouse
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Concanavalin A
  • Interferon-gamma
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Leukocyte Common Antigens