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The Journal of Immunology, 2001, 167: 514-523.
Copyright © 2001 by The American Association of Immunologists

Dissection of the Intracellular Pathways in Hepatocytes Suggests a Role for Jun Kinase and IFN Regulatory Factor-1 in Con A-Induced Liver Failure1

Konrad Streetz, Bastian Fregien, Jörg Plümpe, Kerstin Körber{dagger}, Stefan Kubicka, G. Sass{dagger}, Stephan C. Bischoff, Michael P. Manns, Gisa Tiegs{dagger} and Christian Trautwein2

* Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany; and {dagger} Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen, Erlangen, Germany.

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-{kappa}B 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 IFN regulatory factor-1 and the c-Jun N-terminal kinase pathway are involved in determining hepatocyte damage during Con A-induced liver failure and thus may provide new targets for therapeutic intervention.




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