Involvement of endogenously synthesized interleukin (IL)-18 in the protective effects of IL-12 against pulmonary infection with Cryptococcus neoformans in mice

We previously demonstrated that interleukin (IL)-12 protected mice against fatal pulmonary infection with a highly virulent strain of Cryptococcus neo formans, which correlated well with the production of interferon (IFN)-gamm a as well as IL-18 in the primary infected site. In the present study, we e xamined the role of endogenously synthesized IL-18 in IL-12-induced host re sistance to this pathogen. There was little or no production of IFN-gamma a nd IL-18 both at mRNA and protein levels in lungs of mice infected with C, neoformans, while treatment with IL-IZ induced a marked production of these cytokines. Caspase-1 mRNA was expressed in infected mice even without IL-1 2 treatment. Administration of neutralizing anti-IFN-gamma monoclonal antib ody (mAb) clearly inhibited production of IFN-gamma and TL-18 induced by IL -12, while control IgG did not show such an effect. However, administration of IFN-gamma did not induce the production of both cytokines in infected m ice, although tumor necrosis Factor (TNF)-alpha and IFN-gamma-inducible pro tein (IP)10 were synthesized by the same treatment. Finally, neutralizing a nti-IL-Is antibody (Ab) significantly interfered with the production of IFN -gamma and elimination of the microorganism from the lung induced by IL-12 treatment. Furthermore, both IFN-gamma synthesis and host protection caused by IL-12 were profoundly diminished in IL-18 gene-disrupted mice. Consider ed collectively, our results indicated that host protection against C. neof ormans induced by IL-12 involved endogenously synthesized IL-18 and that th e production of IL-18 was mediated at least in part by endogenous IFN-gamma . (C) 2000 Elsevier Science B.V. All nights reserved.