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*
Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany; and
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-
and IFN-
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- Abs and adenoviral vectors
that express molecules inhibiting distinct TNF--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-- and IFN--dependent intracellular
pathways occurs prior to the influx of immune-activated cells into the
liver and that anti-TNF- and anti-IFN- neutralizing Abs
cannot block infiltration of these cells. Blocking experiments with Abs
and adenoviral vectors showed that NF-
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--dependent expression of IFN regulatory factor-1 and
TNF--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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