EXPRESSION OF CYTOKINES AND INDUCIBLE NITRIC-OXIDE SYNTHASE MESSENGER-RNA IN THE LUNGS OF MICE INFECTED WITH CRYPTOCOCCUS-NEOFORMANS - EFFECTS OF INTERLEUKIN-12

We have recently established a murine model of pulmonary and dissemina ted infection with a highly virulent strain of Cryptococcus neoformans and demonstrated that administration of interleukin-12 (IL-12) protec ted the animals against infection. In this study, we extended these st udies by investigating the host defense mechanisms. In particular, we examined the expression of mRNA for helper T-cell 1 (Th1) cytokines (I L-2, lymphotoxin, and gamma interferon [IFN-gamma]), Th2 cytokines (IL -4, -6, and -10), macrophage-derived cytokines (tumor necrosis factor alpha [TNF-alpha], IL-1 beta, transforming growth factor beta [TGF-bet a], IL-12p40, and IFN-gamma-inducing factor [IGIF]), and inducible nit ric oxide synthase (iNOS) in the lungs on days 1, 3, 7, and 14 after i nfection and following treatment with IL-12. There was little or no ex pression of mRNAs for Th1 cytokines, TNF-alpha, IL-12p40, IGIF, and iN OS in the infected mice, but expression increased markedly after treat ment with IL-12. In contrast, the mRNAs for Th2 cytokines, IL-1 beta, and TGF-beta were detected at considerable levels during the early sta ges of infection, and, interestingly, expression was not suppressed by IL-12 but rather augmented, particularly during the late stage. Simil ar results were also obtained for IFN-gamma, IL-4, IL-10, and TNF-alph a measured in the lung homogenates by enzyme-linked immunosorbent assa y. These results suggest that the predominance of expression of Th2 cy tokines and TGF-beta over Th1 cytokines, TNF-alpha, IL-12p40, IGIF, an d iNOS is associated with severe lethal infection in mice and that adm inistration of IL-12 protects infected animals by stimulating Th1 cyto kines.