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-gamma]), Th2 cytokines (IL-4, -6, and -10), macrophage-derived cytokines (tumor necrosis factor alpha [TNF-alpha], IL-1beta, transforming growth factor beta [TGF-beta, IL-12p40, and IFN-gamma-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-alpha, 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-1beta, and TGF-beta 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-gamma, IL-4, IL-10, and TNF-alpha measured in the lung homogenates by enzyme-linked immunosorbent assay. These results suggest that the predominance of expression of Th2 cytokines and TGF-beta over Th1 cytokines, TNF-alpha, 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.
Kawakami
K
K
First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
Tohyama
M
M
Qifeng
X
X
Saito
A
A
D000818:Animals; D003453:Cryptococcosis / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D018664:Interleukin-12 / Q000008:administration & dosage*; D008168:Lung / Q000382:microbiology*; D051379:Mice; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis*; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism
D016207:Cytokines; D012333:RNA, Messenger; D018664:Interleukin-12; D019001:Nitric Oxide Synthase