Dissection of the Intracellular Pathways in Hepatocytes Suggests a Role for Jun Kinase and IFN Regulatory Factor-1 in Con A-Induced Liver Failure

• Published in: The Journal of immunology (1950) Vol. 167; no. 1; pp. 514 - 523
• Main Authors: Streetz, Konrad, Fregien, Bastian, Plumpe, Jorg, Korber, Kerstin, Kubicka, Stefan, Sass, G, Bischoff, Stephan C, Manns, Michael P, Tiegs, Gisa, Trautwein, Christian
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.07.2001
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Carrier Proteins - metabolism; CD4-Positive T-Lymphocytes - pathology; Cell Movement - immunology; concanavalin A; Concanavalin A - administration & dosage; Concanavalin A - pharmacology; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; fas Receptor - metabolism; 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; JNK protein; 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; Signal Transduction - immunology; STAT1 Transcription Factor; Trans-Activators - antagonists & inhibitors; Trans-Activators - metabolism; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.167.1.514

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