Murine concanavalin A-induced hepatitis is prevented by interleukin 12 (IL-12) antibody and exacerbated by exogenous IL-12 through an interferon-gamma-dependent mechanism

Concanavalin A (ConA)-induced hepatitis is a cell-mediated immunoinflammato ry condition similar to human autoimmune hepatitis. We investigated the rol e of interleukin 12 (IL-12) in hepatitis induced in NMRI and C57/BL6 mice b y a single injection of ConA. Recombinant murine IL-12 administered 24 hour s and 1 hour prior to ConA exacerbated both transaminase activities in plas ma and histologic signs of hepatitis. These markers of liver injury were si gnificantly reduced by prophylactic, hut not therapeutic treatment with ant i-IL-12 monoclonal antibody (mAb). The disease-modulatory effects of IL-12 and anti-IL-12 mAb were associated with profound and reverse modifications of a ConA-induced increase in the circulating levels of IL-4, IL-6, interfe ron gamma (IFN-gamma) and tumor necrosis factor (TNF). Relative to control animals receiving ConA alone, the plasma levels of these cytokines were all augmented in IL-12/ConA-treated mice and diminished in anti-IL-12 mAb/ Con A-treated mice. Anti-IFN-gamma mAb also impeded the appearance of IL-12/Con A-induced hepatitis. Thus, IL-12-induced production of IFN-gamma might play a role in mediating the hepatitis-inducing effect of ConA. However, IL-12p 40-deficient C57/BL6 mice were as susceptible as wild-type controls to the hepatitis-inducing effect of ConA.