IL-10 Regulates Mast Cell Function and Survival

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DESCRIPTION (provided by applicant): Our proposal will investigate the clinically important area of mast cell homeostasis. Mast cells are well-known for their role in allergy and asthma, and have recently been implicated in inflammatory disorders such as multiple sclerosis, arthritis, and heart disease. A critical gap in the understanding of inflammatory disease is how the mast cell response is normally dampened to prevent chronic inflammation. Our hypothesis is that IL-10 is an endogenous mediator of mast cell homeostasis. We present clear evidence that IL-10 suppresses the function and survival of mouse and human mast cells. Preliminary in vivo studies corroborate these data. We also show that IL-10 may be provided by two sources: (I) autocrine production from activated mast cells, and (II) paracrine production from CD25+ regulatory T cells (Treg). Manipulating mast cell homeostasis could be a powerful tool for the treatment of inflammatory disease. Our Specific Aims are: I. To determine how IL-10 suppresses IgE receptor expression and function in vitro and in vivo. We will test the following hypotheses: A. IL-10 employs Stat5 to inhibit Fc?RI function, by suppressing Syk, Akt, and Stat5 expression. B. IL-10 suppresses Fc?RI expression in vivo, and mitigates IgE-mediated anaphylaxis. C. IL-10 is provided by activated mast cells and by recruited Tregs. D. Tregs suppress mast cell function in vivo by producing IL-10. II. To determine how IL-10 inhibits mast cell proliferation and survival in vitro and in vivo. We will test the following hypotheses: A. IL-10 induces cell cycle arrest and apoptosis in mast cells by inhibiting Stat5 and Akt expression. B. Tregs inhibit mast cell proliferation and survival by secreting IL-10. C. IL-10, possibly derived from Tregs, suppresses mast cell hyperplasia in vivo.