Critical Involvement of Interferon γ in the Pathogenesis of T–Cell Activation–Associated Hepatitis and Regulatory Mechanisms of Interleukin–6 for the Manifestations of Hepatitis

Abstract

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.