A single intravenous injection of concanavalin A (Con A) induces T-cell activation and an acute hepatitis in mice. This study investigated the role of interferon γ (IFN-γ) in the pathogenesis of this hepatitis model. Striking increases in the plasma levels of various cytokines, including tumor necrosis factor (TNF), interleukin-2 (IL-2), and IFN-γ, were detected before the increase in plasma aminotransferase levels induced by Con A injection. TNF levels peaked within 2 hours, whereas IFN-γ levels peaked at 6 hours after Con A injection. In contrast to a sharp peak of TNF levels, high IFN-γ levels were detected for a more prolonged period. Passive immunization with anti-IFN-γ monoclonal antibody (MAb) conferred a dose-dependent protection against liver injury in this model. This protection was observed when anti-IFN-γ MAb was administered at least 30 minutes before Con A injection but not when given 1 hour after Con A injection. The protection from Con A-induced hepatitis was also induced by administration of rIL-6 before Con A injection. rIL-6 treatment induced significant albeit incomplete inhibition of IFN-γ and TNF production, whereas this regimen did not affect IL-2 production. Despite striking protective effects of rIL-6 or anti-IFN-γ MAb, comparable levels of cellular (both T cell and polymorphonuclear cell) infiltration were detected in liver sections from animals untreated, or treated with either rIL-6 or anti-IFN-γ MAb. Moreover, electron microscopic examination showed that infiltrating T cells exhibited a blastoid appearance in all groups. These results indicate that IFN-γ plays a critical role in the development of Con A-induced acute hepatitis and suggest that IL-6 administration can regulate the manifestation of hepatitis through mechanisms including the reduced production of inflammatory cytokines such as IFN-γ.