Most recently, the production of Th17 cytokines by macrophages and its suppression by IL-10 was shown in vitro using IL-10R2 deficient macrophages 23. By using IL-10R1 knock-out mice, we could confirm that the suppression of IL-17 production is IL-10 specific and that monocytes/macrophages are the main targets of IL-10 in the regulation of the Th17 cytokine production. Knowing that the main Palbociclib mw target of IL-10 in the regulation of the innate immune response to LPS are monocytes/macrophages and/or neutrophils, we proceeded to examine which cell type is the main target in the adaptive immune response to T. muris infection. Worm burdens were equal in wt and IL-10R+/−

mice (data not shown). IL-10R−/− mice displayed an increased worm burden at day 21 and 35 post-infection when compared with IL-10R+/− littermates. The increased worm burden was similar to that seen in IL-10−/−

(Fig. 3A and B). The macrophage and neutrophil-specific deletion of IL-10R1 led to a slightly increased worm burden at day 21. No differences in worm burden were observed for IL-10RFl/FlCd4-Cre+versus Cre− littermates. Nevertheless, all IL-10R1 conditional knock-out mouse strains analysed had expelled the worms at day 35 post-infection (Fig. 3A and B). Histological caecum scores revealed no increased inflammation U0126 datasheet in IL-10RFl/FllysMCre+ mice. Taken together, the lack of IL-10R1 in T cells did not influence the susceptibility to T. muris infection. The lack of IL-10R1 in monocytes, macrophages and neutrophils resulted in a slightly delayed but still successful expulsion of the worms. While we have shown earlier, that T-cell-derived IL-10 is an inhibitor of the Th1 immune response in the T. muris E-isolate infection model 24, we show here that T cells are not the main responder to IL-10 in this model. This was surprising because T cells are known to regulate the Th1 immune response in a self-regulatory autocrine loop (reviewed in 25). A slight mafosfamide effect of the deletion of IL-10R1

in monocytes, macrophages and neutrophils was observed, leading to higher worm burden at day 21. Nevertheless, the mice were able to expel the worms by day 35, leading to the conclusion that further cell types must act synergistically. Thus, in the regulation of the Th1 immune response, neither T cells nor monocytes/macrophages and neutrophils alone are the crucial targets of IL-10. Whether IL-10R signalling in DC, epithelial cells, basophils or a combination of effector cells is necessary in this model remains speculative. We have generated a novel IL-10R1 conditional knock-out mouse strain to assess the cell type specific function of IL-10R signalling. Our data demonstrate that for the regulation of the innate immune response to LPS, IL-10R signalling in monocytes/macrophages and/or neutrophils is crucial.