A PIVOTAL ROLE OF IL-12 IN T(H)1-DEPENDENT MOUSE-LIVER INJURY

Intravenous injection of Propionibacterium acnes and lipopolysaccharid e (LPS) with a 7 day interval caused CD4(+) T cell-dependent severe li ver injury in the C57BL/6 (H-2(b)) mouse strain, In contrast, BALB/c ( H-2(d)) mice were resistant to P. acnes and LPS-induced liver injury, The different susceptibilities of the two mouse strains to liver injur y appeared to be closely correlated with their different abilities to produce IFN-gamma after P. acnes priming, Namely, the sensitive C57BL/ 6 mouse strain produced a significant level of IFN-gamma 7-10 days aft er P. acnes injection, whereas no significant amount of serum IFN-gamm a was detected in the resistant BALB/c mouse strain, The important rol e of IFN-gamma in liver injury was demonstrated from the finding that in vivo administration of anti-IFN-gamma mAb abrogated P. acnes and LP S-induced liver injury in C57BL/6 mice. Moreover, it was demonstrated that in vivo administration of recombinant IL-12, a key cytokine for t he induction of IFN-gamma, into mice induced P. acnes and LPS-induced liver injury in the resistant BALB/c mouse strain, Conversely, in vivo administration of anti-IL-12 mAb blocked the development of liver inj ury in the sensitive C57BL/6 mouse strain, Moreover, it was demonstrat ed that the failure of the induction of liver injury in BALB/c mice ap peared to be derived from the lack of expression of IL-12 at the local site of liver in P. acnes-primed mice. These results strongly indicat ed that endogenous IL-12, which stimulates t(h)1-dominant cellular imm unity and IFN-gamma production, may be an essential cytokine on the co urse of T cell-dependent liver injury.