Expression of cytokines and inducible nitric oxide synthase mRNA in the lungs of mice infected with Cryptococcus neoformans: Effects of interleukin- 12

We have recently established a murine model of pulmonary and disseminated infection with a highly virulent strain of Cryptococcus neoformans and demonstrated that administration of interleukin-12 (IL-12) protected the animals against infection. In this study, we extended these studies by investigating the host defense mechanisms. In particular, we examined the expression of mRNA for helper T-cell 1 (Th1) cytokines (IL-2, lymphotoxin, and gamma interferon [IFN-γ]), Th2 cytokines (IL-4, -6, and - 10), macrophage-derived cytokines (tumor necrosis factor alpha [TNF-α], IL- 1β, transforming growth factor β [TGF-β], IL-12p40, and IFN-γ-inducing factor [IGIF]), and inducible nitric oxide synthase (iNOS) in the lungs on days 1, 3, 7, and 14 after infection and following treatment with IL-12. There was little or no expression of mRNAs for Th1 cytokines, TNF-α, IL- 12p40, IGIF, and iNOS in the infected mice, but expression increased markedly after treatment with IL-12. In contrast, the mRNAs for Th2 cytokines, IL- 1β, and TGF-β were detected at considerable levels during the early stages of infection, and, interestingly, expression was not suppressed by IL-12 but rather augmented, particularly during the late stage. Similar results were also obtained for IFN-γ, IL-4, IL-10, and TNF-α measured in the lung homogenates by enzyme-linked immunosorbent assay. These results suggest that the predominance of expression of Th2 cytokines and TGF-β over Th1 cytokines, TNF-α, IL-12p40, IGIF, and iNOS is associated with severe lethal infection in mice and that administration of IL-12 protects infected animals by stimulating Th1 cytokines.