Bimodal role of endogenous interleukin-6 in concanavalin A-induced hepatitis in mice

Acute concanavalin A (Con A)-induced hepatitis in mice is an animal model f or hepatic injury induced by activated T cells. The evolution of hepatic in volvement can be followed from hour to hour by measuring serum transaminase levels. We investigated the possible role of endogenous interleukin-6 (IL- 6) in this model, We found serum IL-6 levels and splenic IL-6 mRNA during C on A-induced hepatitis to be significantly lower in interferon-gamma (IFN-g amma)-deficient mice, which are resistant against the Con A-induced syndrom e, than in wild-type ones, suggesting that systemic IL-Ci production favors development of hepatic injury. However, IL-6-deficient mice proved to be m ore susceptible to the disease than wild-type mice, indicating that endogen ous IL-6 plays a predominantly hepatoprotective role. Experiments in which wild-type mice were treated with anti-IL-Ci antibodies, before or after Con A challenge, allowed us to reconcile these contrasting observations. The a ntibody injections resulted in a biphasic alteration of serum IL-6 levels, initial neutralization being followed by rebound increased levels due to ac cumulation of IL-6 in tbe form of antigen-antibody complexes, The effect of antibody on disease severity differed depending on tbe time of injection. Antibody injection at 2.5 h post Con A resulted in delayed disease manifest ation, whereas treatment initiated before Con A resulted in accelerated dis ease. We conclude that endogenous IL-6 plays a bimodal role. IL-6 present b efore Con A challenge as well as that induced in the very early phase after Cell A injection triggers hepatoprotective pathways. Continuation of IL-6 production. beyond this early phase, by some other pathway, seems to be har mful to hepatocytes.