Impaired resistance to the development of toxoplasmic encephalitis in interleukin-6-deficient mice.

Abstract

The role of interleukin-6 (IL-6) in the pathogenesis of toxoplasmic encephalitis (TE) was examined by using IL-6-targeted mutant (IL-6(-/-)) mice. At 4 and 8 weeks after infection with the ME49 strain of Toxoplasma gondii, significantly greater numbers of T. gondii cysts and areas of inflammation associated with tachyzoites were observed in brains of IL-6(-/-) mice than in those of control mice. Large areas of necrosis were observed only in brains of IL-6(-/-) mice. Tachyzoites were frequently detected in the areas of necrosis, suggesting that necrosis was caused by proliferation of the parasite. These results indicate that IL-6 is protective against development of TE by preventing formation of T. gondii cysts and proliferation of tachyzoites in brains of infected mice. Whereas in brains of control mice, large numbers of inflammatory cells were always observed in areas where tachyzoites were detected, in brains of IL-6(-/-) mice, only small numbers of inflammatory cells were observed in many areas with tachyzoites. Lymphocyte preparations isolated from brains of infected control mice had significantly higher ratios of gamma/delta T cells and CD4+ alpha/beta T cells but lower ratios of CD8+ alpha/beta T cells compared to those of infected IL-6(-/-) mice. There were no differences in the ratios of these T-cell subsets in spleens between these mice. The amounts of mRNA for gamma interferon (IFN-gamma) detected by reverse transcriptase PCR were significantly smaller in brains of IL-6(-/-) mice than in those of control mice, whereas amounts of IL-10 mRNA were greater in the former than in the latter. IL-6 mRNA was detected only in infected control mice. The protective activity of IL-6 against development of TE appears to be through its ability to stimulate IFN-gamma production and induce infiltration and accumulation of different T-cell subsets in brains of infected mice.