SummaryInitial studies on the biology of IL-27 provided evidence of a role for this cytokine in the initiation of Th1 responses; however, subsequent work using models of pathogen-induced and autoimmune inflammation have indicated that IL-27 has broad inhibitory effects on Th1, Th2 and Th17 subsets of T cells as well as the expansion of inducible regulatory T cells. While, the aim of this review is to highlight the functions of IL-27 in the context of inflammation it will also serve to elaborate on the molecular mechanisms involved in the production of this cytokine. The initial description of IL-27 indicated that classical antigen-presenting cells such as macrophages and dendritic cells produce IL-27, however, the agonists and signaling pathways involved in activating transcription of the two subunits of IL-27, p28 and EBV-induced gene 3 (EBI3) have only recently been described.

Previous studies of mice have implicated natural killer (NK) cells as mediators of protective activity against Toxoplasma gondii through their production of gamma interferon (IFN-y). In the present study, we have compared NK-cell activity in infected and uninfected SCID mice. Our data reveal that infection results in increased levels of IFN-y in serum and elevated NK-cell activity but that these NK cells were not cytotoxic for T. gondii-infected P815 cells. Treatment with anti-IFN-y antibody abrogated the increase in NK-cell activity and resulted in earlier mortality of infected mice. In vivo treatment with anti-asialo GM1 antiserum reduced NK cell activity and levels of IFN-y in serum but did not alter time to death. Spleen cells from infected mice produced higher levels of IFN-y than those from uninfected mice when stimulated in vitro with live T. gondii or parasite antigen preparations. Further analysis revealed that interleukin 10 (IL-10) inhibited, whereas tumor necrosis factor alpha (TNF-a) and IL-12 enhanced, IFN-y production by spleen cells from infected or uninfected mice. The combination of IL-12 and TNF-a induced higher levels of IFN-y from whole spleen cells of infected mice than from those of uninfected mice. Depletion of the adherent cell population from the spleen cells of infected mice led to a significant reduction in the levels of IFN-.y produced after stimulation with IL-12 plus TNF-at. Similar results did not occur with cells from uninfected mice. These data indicate that other cytokines produced by the adherent cell population from infected mice may be involved in maximal production of IFN-,y by NK cells stimulated with IL-12 and TNF-ce. To assess the importance of endogenous IL-12, a polyclonal anti-IL-12 was administered to infected SCID mice. This treatment led to earlier mortality, indicating that endogenous IL-12 mediates resistance to T. gondii.

The interaction of host cells with microbial products or their invasion by pathogens frequently results in activation of the NF-kappaB family of transcription factors. The studies presented here reveal that in vivo, infection with Toxoplasma gondii results in the activation of NF-kappaB. To determine whether host cells could activate NF-kappaB in response to invasion by T. gondii, Western blots, immunofluorescence, and electrophoretic mobility shift assays were used to assess the response of host cells to infection. In these studies, infection of macrophages or fibroblasts with T. gondii did not result in the activation of NF-kappaB. In addition, the ability of lipopolysaccharide to activate NF-kappaB was impaired in cultures of macrophages infected with T. gondii. Together, these data demonstrate that invasion of cells by T. gondii does not lead to the activation of NF-kappaB and suggest that the parasite may actively interfere with the pathways that lead to NF-kappaB activation.

Interleukin-10 (IL-10) is a cytokine which can inhibit T-cell and natural killer (NK) cell functions associated with cell-mediated immunity to intracellular infections. The production of IL-10 by mice infected with Toxoplasma gondii has been implicated in the suppression of lymphocyte proliferation observed during acute toxoplasmosis, as well as susceptibility to infection with this parasite. We have used C57BL/6 mice which lack a functional IL-10 gene (IL-10 ؊/؊ mice) to investigate the role of IL-10 in acute toxoplasmosis. Intraperitoneal infection of IL-10 ؊/؊ mice with T. gondii resulted in 100% mortality by day 13, whereas wild-type C57BL/6 (WT) mice survived acute infection. IL-10 ؊/؊ mice infected with T. gondii had significantly higher serum levels of IL-12 and gamma interferon (IFN-␥) than WT mice. Early mortality of infected IL-10 ؊/؊ mice was prevented by treatment with IL-10 and significantly delayed by neutralizing antibodies to IL-12 and IFN-␥. Further studies revealed that SCID/IL-10 ؊/؊ mice infected with T. gondii had delayed time to death compared to IL-10 ؊/؊ mice, indicating that lymphocytes contributed to death of IL-10 ؊/؊ mice. In addition, infected SCID/IL-10 ؊/؊ mice survived longer than infected SCID mice. These latter data indicate that in mice lacking lymphocytes, endogenous IL-10 is associated with increased susceptibility to T. gondii. However, the lack of IL-10 does not alter the infection-induced suppression of T cell and NK cell functions. Our experiments reveal that IL-10 is associated with protection or increased susceptibility to infection with T. gondii, depending on whether mice possess lymphocytes, and demonstrate the important roles of IL-12 and IFN-␥ in the early infection-induced mortality observed in the IL-10 ؊/؊ mice.

The incidence of toxoplasmic encephalitis (TE) has increased with the increasing numbers of patients with immunodeficiencies, in whom reactivation of latent Toxoplasma infection may occur. This highlights the important role of the immune response in maintaining infection with Toxoplasma gondii in a latent form. Because the brain is the most commonly affected site of latent infection and because it is anatomically unique in regard to the immune system, understanding the systemic immune response to infection within the brain is important. Murine models have proven useful for the study of the immune response to T. gondii and identified the importance of cytokines and NK and T cells in the regulation of protective immunity to T. gondii. Further studies on the development of TE have indicated the possible importance of the interactions of glial cells, such as microglia and astrocytes, with infiltrating T cells to mediate immunity to T. gondii within the brain.