Combined stimulation with the T helper cell type 2 cytokines interleukin (IL)-4 and IL-10 induces mouse mast cell apoptosis

Mast cells are found in connective and mucosal tissues throughout the body. Their activation via immunoglobulin E (IgE)-antigen interactions is promot ed by T helper cell type 2 (Th2) cytokines and leads to the sequelae of all ergic disease. We now report a mechanism by which Th2 cytokines can regulat e mast cell survival. Specifically, we find that interleukin (IL)-4 and IL- 10 induce apoptosis in IL-3-dependent bone marrow-derived mast cells and pe ritoneal mast cells. This process required 6 d of costimulation with IL-3, IL-4, and IL-10, and expression of signal transducer and activator of trans cription 6 (Stat6). Apoptosis was coupled with decreased expression of bcl- x(L) and bcl-2. While this process occurred independent of the Fas pathway, culture in IL-3+IL-4+IL-10 greatly sensitized mast cells to Fas-mediated d eath. Additionally, we found that IgE cross-linkage or stimulation with ste m cell factor enhanced the apoptotic abilities of IL-4 and IL-10. Finally, IL-3-independent mastocytomas and mast cell lines were resistant to apoptos is induced by IL-3+IL-4+IL-10. These data offer evidence of Th2 cytokine-me diated homeostasis whereby these cytokines both elicit and limit allergic r esponses. Dysregulation of this pathway may play a role in allergic disease and mast cell tumor survival.