| Outside of the Toll-like-receptor paradigm, there is little understanding of how pathogen recognition at the cell surface is linked to functional responses in cells of the innate immune system. Recent work in this area demonstrates that the yeast particle zymosan, by binding to the C-type lectin and beta-glucan receptor Dectin-1, activates an ITAM-Syk-dependent signaling pathway in dendritic cells, which is required for optimal cytokine production, generation of an oxidative burst, and the ultimate eradication of yeast pathogens in mouse models of infection. It remains unclear how activation of Syk is coupled to downstream effector mechanisms. Here, we provide evidence that, in human primary macrophages, zymosan triggers activation of calcium- and Pyk2-dependent signaling pathways, which are required for production of the anti-inflammatory cytokine IL-10. Furthermore, we implicate reactive oxygen species as a novel player in the complex regulation of IL-10 production. These observations describe novel pathways activated by zymosan and link these pathways to a key macrophage function which is incompletely understood, production of the immunoregulatory molecule IL-10.;IL-10 is produced by macrophages in response to a pathogenic stimulus and functions mainly to limit the production of inflammatory mediators, preventing an excessive or prolonged inflammatory response. However, anti-inflammatory IL-10 activity must be kept in check during the early stages of an infection in order to allow for proper microbial recognition and subsequent recruitment of other leukocytes, which allow for clearance of the pathogen. The way in which IL-10 function is regulated during an immune response is not completely understood. We have uncovered a novel and rapid mechanism for inhibition of IL-10-induced STAT3 tyrosine phosphorylation by a commonly studied yeast particle, zymosan. Zymosan specifically inhibits IL-10-mediated signaling and gene expression via a PKCbeta-and PI3-kinase dependent mechanism in human macrophages. Interestingly, inhibition is dependent on zymosan recognition by the beta-glucan receptor, Dectin-1, but is independent of other receptors known to mediate inflammatory responses to zymosan.;Together, these results delineate intricate mechanisms for regulation of IL-10 production and function in innate immune cells, providing insight into the complexities of pathogen-host interactions and offering novel targets for future development of therapies for many inflammatory diseases. |
