Testing whether type I IFNs drive this STAT4 pathway

Testing whether type I IFNs drive this STAT4 pathway selleck screening library was one motivation for these

investigations. In our current studies, IFN-α/βR KO mice had an early defect in IFN-γ production in response to L. mexicana antigens. We found that at 4 weeks of infection, the already weak IFN-γ response seen in WT mice is further diminished when IFN-α/β signalling is lacking. This indicates that IFN-α/β does have a role in promoting Th1 development and could act through STAT4 in this process. However, later in infection, there is no lasting effect on IFN-γ (perhaps because the WT mice have decreased IFN-γ) and the overall course of lesion progression, parasite burdens, and nitric oxide production were not different in IFN-α/βR KO and WT mice. This transient importance of IFN-α/β has several potential mechanisms. Others have found that Type I IFNs can induce STAT4 phosphorylation in mice but that it is less sustained than from IL-12 stimulation, and thus does not, in and of itself, induce Th1 development. In addition, IFN-α can increase IFN-γ synergistically with IL-18 from Th1 cells (21). This less sustained nature of STAT4 signalling may contribute LY2835219 clinical trial to a lack of sustained effects on IFN-γ. IFN-α/β has been shown to decrease IL-12 strongly (18,19) and thus decrease Th1 development and IFN-γ from CD4+ T cells, as well as from NK cells. Therefore, IFN-α/βR KO mice may have increased IL-12-induced STAT4 activation offsetting the lack of the IFN-α/β-driven

IL-12-independent STAT4 pathway. However, we did not see higher IL-12 levels in the serum of L. mexicana-infected Glutathione peroxidase mice making this hypothesis less likely. Later, in infection, serum IgG1, which has a delayed kinetics, is present and is able to induce IL-10 through FcγR (22) suppressing the development of a Th1 response. An early worsening of disease caused by L. major was seen in a strain of mice that is naturally

a low IFN-α/β producer (10). As in our studies, the final disease outcome was not changed by a decrease in type I IFNs indicating that there is redundancy and that type I IFNs do not drive the dominant pathway. We also found that IFN-α/βR KO mice have a defect in IL-10 production from draining lymph node cells. The ELISA data were corroborated by a decrease in IL-10 mean fluorescence intensity in CD25+CD4+ T cells, the main CD4+ T cell population that produces IL-10, and possibly a decrease in the percentage of IL-10 producing cells. There is some earlier evidence that IFN-α/β can induce IL-10, at least in humans (23,24). Our current data support the idea that mice also have this mechanism of IFN-α/β induction of IL-10. Thus, type I IFNs could work towards increased susceptibility through IL-10 stimulation, thus blunting some of the protective effects of IFN-α/β signalling through STAT4. We found that IFN-α/βR KO mice had an early increase in parasite-specific IgG1 and IgG2a and yet had less LN T cell IL-10 throughout the infection.

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