Inhibition of concanavalin A-induced hepatic injury of mice by bacterial lipopolysaccharide via the induction of IL-6 and the subsequent reduction of IL-4: the cytokine milieu of concanavalin A hepatitis

Background/Aims: Liver natural killer 1.1 antigen (NK1)+ T cells and IL-4 play a crucial role in concanavalin-A (Con-A)-induced hepatic injury in mice, and a T helper (Th) 2 immune response was thus suggested to be involved. This study was designed to examine the effect of bacterial lipopolysaccharide (LPS), a strong inducer of a Th 1 immune response, on Con-A hepatic injury and also to clarify further the cytokine milieu of Con-A hepatitis. Methods: LPS were injected into mice before Con-A injection to evaluate the effect on hepatic injury. The effect of the pretreatment with various T1 and Th2 cytokines or anti-cytokine antibodies on Con-A hepatitis was also examined. Results: LPS in quantities 500 ng/mouse, when injected 24 h before Con-A injection, abrogated the Con-A-induced elevation of transaminases, hepatocyte destruction and serum IL-4 elevation. This LPS inhibitory effect was blocked when the mice were injected with either anti-IL-6 antibody before LPS injection or IL-4 before Con-A injection. IL-6, but neither IL-10 nor IL-12 pretreatment suppressed Con-A-induced IL-4 production and hepatitis. NK1+ T cells produced IL-4 while both NK1+ T cells and NK1− T cells produced IFN-γ. Not only anti-IL-4 antibody but also the anti-IFN-γ antibody pretreatment inhibited Con-A hepatitis. However, although the anti-IL4 antibody suppressed IL-4 alone, the anti-IFN-γ Ab unexpectedly inhibited both IFN-γ and IL-4 elevation, while IL-4 injection evoked a moderate Con-A hepatitis even in the anti-IFN-γ antibody-treated mice. Furthermore, the IL-4 mutant mice did not develop Con-A hepatitis. Conclusion: LPS inhibited Con-A hepatitis by inducing IL-6 and thereby inhibited IL-4 synthesis from NK1+ T cells. Although both IL-4 and IFN-γ were required for the full induction of Con-A hepatic injury, exogenous IL-4 evoked a moderate Con-A hepatitis, even in the absence of IFN-γ.