Concanavalin A-induced hepatitis in mice is prevented by interleukin (IL)-10 and exacerbated by endogenous IL-10 deficiency

One single intra-venous (i.v.) injection of Concanavalin A (Con A) into mic e provokes a cell-mediated immunoinflammatory hepatitis. We have presently evaluated the immunopharmacological effects of exogenous interleukin (IL)-1 0 and the role of endogenous IL-10 in this model by using exogenous IL-10, anti-IL-10 monoclonal antibody (mAb) and mice with disrupted IL-10 gene (IL -10 KO mice). Whilst exogenous IL-10 administered in a prophylactic (1 h pr ior to Con A) and even "early" therapeutic fashion (30 min after Con A) red uced the elevation of transaminase activities in plasma in a dose-dependent manner, observed in control mice, these biochemical markers; of liver inju ry were significantly increased both in IL-10 KO mice as well as in those r eceiving anti-IL-10 mAb, Interestingly, doses of Con A lower than 20 mg/kg that were only capable of inducing slight serological signs of hepatitis in mice, exerted marked hepatitic effects when administered to either anti-IL -10 mAb-treated mice or to IL-10 KO mice. The disease modulating effects of exogenous IL-10 and either genetical or pharmacologically-induced IL-IO de ficiency were associated with profound and opposite modifications of the Co n A-induced increase in the circulating levels of IFN-gamma and TNF-alpha. Relative to control animals, the blood levels of these cytokines were dimin ished in IL-10-treated mice and augmented in both IL-10 KO mice and anti-IL -10 mAb-treated mice. These results prove the physiological antiinflammator y role of endogenous IL-10 in Con A induced hepatitis and the beneficial ef fects of IL-10 treatment to prevent this condition.