The role of recombinant murine IL-12 and IFN-gamma in the pathogenesis of a murine systemic Candida albicans infection.
Studies on murine candidiasis suggest that resistance to disease is linked to a Th1 response and production of IFN-gamma, while failure to elicit protection is associated with a Th2 response and production of IL-4 and IL-10. Experimental infection of C57BL/6 mice, IL-12 treatment of these mice, or both infection and IL-12 treatment resulted in a characteristic Th1 cytokine mRNA profile as measured by quantitative competitive PCR. Specifically, little or no IL-4 transcripts were detected, while IFN-gamma message was elevated, particularly with IL-12 treatment. Despite its role in driving increased IFN-gamma expression and production, IL-12 treatment, paradoxically, promoted disease progression in our model. Therefore, we examined the effect of IFN-gamma neutralization on IL-12-induced susceptibility to infection. None of the systemically infected mice receiving IL-12 alone survived, while IL-12- and anti-IFN-gamma-treated mice had a 70% survival rate, similar to that after infection alone. These results suggested that IFN-gamma induced by IL-12 treatment contributed to lethality. However, in separate studies, IFN-gamma knockout mice were more susceptible to infection than their wild-type counterparts, suggesting that IFN-gamma is required for resistance. Nonetheless, infected IFN-gamma knockout mice treated with recombinant murine IL-12 exhibited enhanced resistance, suggesting that the toxicities observed with IL-12 are directly attributable to IFN-gamma and that an optimal immune response to Candida infections necessitates a finely tuned balance of IFN-gamma production. Thus, we propose that although IFN-gamma can drive resistance, the overproduction of IFN-gamma during candidiasis, mediated by IL-12 administration, leads to enhanced susceptibility.
Lavigne
L M
LM
Department of Preclinical Research and Development, Genetics Institute, Inc., Andover, MA 01810, USA.
Schopf
L R
LR
Chung
C L
CL
Maylor
R
R
Sypek
J P
JP
D000818:Animals; D002176:Candida albicans; D002177:Candidiasis / Q000276:immunology*; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000494:pharmacology*; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology / Q000502:physiology*; D015847:Interleukin-4 / Q000378:metabolism; D007668:Kidney / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins; D013154:Spleen / Q000276:immunology; D016019:Survival Analysis
D018076:DNA, Complementary; D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma