Interferon gamma plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A.
OBJECTIVE
T cell-dependent liver injury involving endogenous tumor necrosis factor (TNF) alpha can be induced by either concanavalin A in naive mice or by activating anti-CD3 antibody or staphylococcal enterotoxin B in D-galactosamine-sensitized mice. In this study, the role of interferon gamma (IFN-gamma) in these T-cell models was addressed.


METHODS
Mice were pretreated with a neutralizing anti-mouse IFN-gamma antiserum before injection of T cell-activating agents. Plasma cytokine and transaminase levels were determined. Apoptotic cell death was assessed by hepatic DNA fragmentation.


RESULTS
Anti-IFN-gamma antiserum significantly protected mice from concanavalin A-induced liver injury. Circulating IFN-gamma was completely suppressed, and TNF was reduced by 50%. Recombinant TNF-alpha administered to mice treated with concanavalin A and anti-IFN-gamma antiserum failed to initiate liver injury. Similar results were obtained with recombinant IFN-gamma in concanavalin A-challenged mice under the condition of TNF neutralization. Neither hepatic DNA fragmentation nor release of transaminases was inhibited by anti-IFN-gamma antiserum when liver injury was induced by staphylococcal enterotoxin B or anti-CD3 antibody in D-galactosamine-sensitized mice.


CONCLUSIONS
Both TNF as well as IFN-gamma are critical mediators of liver injury in concanavalin A-treated mice, whereas hepatic DNA fragmentation and liver failure in the D-galactosamine models depend only on TNF.
Küsters
S
S
Biochemical Pharmacology, Faculty of Biology, University of Konstanz, Germany.
Gantner
F
F
Künstle
G
G
Tiegs
G
G
D000818:Animals; D017209:Apoptosis; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D003208:Concanavalin A / Q000009:adverse effects*; D004249:DNA Damage; D004768:Enterotoxins / Q000009:adverse effects; D004797:Enzyme-Linked Immunosorbent Assay; D005688:Galactosamine / Q000009:adverse effects; D007106:Immune Sera / Q000494:pharmacology; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D017093:Liver Failure / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000502:physiology*; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology
D004768:Enterotoxins; D007106:Immune Sera; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; C031818:enterotoxin B, staphylococcal; D005688:Galactosamine; D007371:Interferon-gamma; D000637:Transaminases