Interleukin-10 enhances IL-33-mediated MC activation and modulates the development of food allergy

Abstract

Abstract We recently demonstrated an unexpected, proinflammatory role for the pleiotropic cytokine, IL-10, in promoting mast cell (MC) responses during food allergy. IL-10 enhanced MC proliferation and survival and promoted IgE-dependent responses to enteric ovalbumin (OVA) challenge. However, whether the effects of IL-10 on MCs extend beyond IgE-mediated signaling is not clear. To determine whether IL-10 can prime MC activation mediated by IgE-independent stimuli, we assessed the effects of rIL-10 on IL-33-stimulated bone marrow-derived MCs (BMMCs) and examined the development of food allergy in IL-10-depleted ST2−/− mice. IL-10 co-culture significantly enhanced the activity and cytokine production of both IgE and IL-33-activated MCs. Furthermore, the production of MC-derived cytokines such as IL-13 was suppressed in IL-33-stimulated IL-10−/− BMMCs, which could be restored by addition of exogenous IL-10. IL-10 enhanced MC FcɛRI and ST2 expression. Further, ST2−/− BMMCs demonstrated that IL-10 enhanced IgE-mediated activation in the absence of autocrine IL-33 signaling. To assess the role of IL-10 in vivo, food allergy was measured in WT and ST2−/− mice subjected to antibody-mediated IL-10 depletion. IL-10-depleted WT mice exhibited a significant attenuation in allergic diarrhea and MC-mediated responses to OVA challenge. Similarly, ST2−/− mice also exhibited a profound suppression of MC-mediated responses, demonstrating the importance of IL-33 in MC regulation. IL-10 depletion had no additional effects in ST2−/− mice. However, IL-10/ST2−/− mice exhibited a further decrease in OVA-IgE and MC activation compared to ST2−/− mice. Our data reveal a novel role for IL-10 in enhancing both IgE and IL-33-mediated MC responses. This project was supported by funds from the National Institutes of Health grants: NIAID R15AI107668 (CBM)