Dissection of the intracellular pathways in hepatocytes suggests a role for Jun kinase and IFN regulatory factor-1 in Con A-induced liver failure.
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
Streetz
K
K
Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany.
Fregien
B
B
Plümpe
J
J
Körber
K
K
Kubicka
S
S
Sass
G
G
Bischoff
S C
SC
Manns
M P
MP
Tiegs
G
G
Trautwein
C
C
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D003208:Concanavalin A / Q000008:administration & dosage* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D053200:Fas-Associated Death Domain Protein; D022781:Hepatocytes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007106:Immune Sera / Q000008:administration & dosage; D007275:Injections, Intravenous; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D007424:Intracellular Fluid / Q000201:enzymology* / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D017093:Liver Failure / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; C494257:IRF1 protein, human; D007106:Immune Sera; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D016328:NF-kappa B; D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D003208:Concanavalin A; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D017493:Leukocyte Common Antigens