Inhibition of concanavalin A-induced hepatic injury of mice by bacterial lipopolysaccharide via the induction of IL-6 and the subsequent reduction ofIL-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-ii (Con-A)-induced hepatic injury in m ice, and a T helper (Th) 2 immune response was thus suggested to be involve d, This study was designed to examine the effect of bacterial lipopolysacch aride (LPS), a strong inducer of a Th 1 immune response, on Con-A hepatic i njury 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 a nd Th2 cytokines or anti-cytokine antibodies on Con-A hepatitis was also ex amined. Results: LPS in quantities greater than or equal to 500 ng/mouse, when inje cted 24 h before Con-A injection, abrogated the Con-A-induced elevation of transaminases, hepatocyte destruction and serum IL-4 elevation, This LPS in hibitory 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 producti on and hepatitis, NK1(+) T cells produced IL-4 while both NK1(+) T cells an d NK1(-) T cells produced TFN-gamma. Not only anti-IL-4 antibody but also t he anti-IFN-gamma antibody pretreatment inhibited Con-A hepatitis, However, although the anti-IL-4 antibody suppressed IL-4 alone, the anti-IFN-gamma Ab unexpectedly inhibited both IFN-gamma and IL-4 elevation, while IL-4 inj ection evoked a moderate Con-A hepatitis even in the anti-IFN-gamma antibod y-treated mice. Furthermore, the IL-4 mutant mice did not develop Con-A hep atitis, Conclusion: LPS inhibited Con-A hepatitis by inducing IL-6 and thereby inhi bited IL-4 synthesis from NK1(+) T cells, Although both IL-4 and IFN-gamma 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-gamma.