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 for hepatic injury induced by activated T cells. The evolution of hepatic involvement 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 Con A‐induced hepatitis to be significantly lower in interferon‐γ (IFN‐γ)‐deficientmice, which are resistant against the Con A‐induced syndrome, than in wild‐type ones, suggesting that systemic IL‐6 production favors development of hepatic injury. However, IL‐6‐deficient mice proved to be more susceptible to the disease than wild‐type mice, indicating that endogenous IL‐6 plays a predominantly hepatoprotective role. Experiments in which wild‐type mice were treated with anti‐IL‐6 antibodies, before or after Con A challenge, allowed us to reconcile these contrasting observations. The antibody injections resulted in a biphasic alteration of serum IL‐6 levels, initial neutralization being followed by rebound increased levels due to accumulation of IL‐6 in the form of antigen‐antibody complexes. The effect of antibody on disease severity differed depending on the time of injection. Antibody injection at 2.5 h post Con A resulted in delayed disease manifestation, whereas treatment initiated before Con A resulted in accelerated disease. We conclude that endogenous IL‐6 plays a bimodal role. IL‐6 present before Con A challenge as well as that induced in the very early phase after Con A injection triggers hepatoprotective pathways. Continuation of IL‐6 production beyond this early phase, by some other pathway, seems to be harmful to hepato‐cytes. J. Leukoc. Biol. 67: 90–96; 2000.M