Interferon gamma plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A

Abstract

Background and Aims: T cell-dependent liver injury involving endogenous tumor necrosis factor (TNF) α 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-γ) in these T-cell models was addressed. Methods: Mice were pretreated with a neutralizing anti-mouse IFN-γ 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-γ antiserum significantly protected mice from concanavalin A-induced liver injury. Circulating IFN-γ was completely suppressed, and TNF was reduced by 50%. Recombinant TNF-α administered to mice treated with concanavalin A and anti-IFN-γ antiserum failed to initiate liver injury. Similar results were obtained with recombinant IFN-γ in concanavalin A- challenged mice under the condition of TNF neutralization. Neither hepatic DNA fragmentation nor release of transaminases was inhibited by anti-IFN-γ 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-γ 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.