IL-10 Regulates Mast Cell Function and Survival

描述(由申请人提供)：我们的建议将研究肥大细胞内稳态的临床重要领域。肥大细胞因其在过敏和哮喘中的作用而广为人知，最近还被认为与多发性硬化症、关节炎和心脏病等炎症性疾病有关。在对炎症性疾病的理解中，一个关键的差距是肥大细胞的反应通常是如何被抑制以防止慢性炎症的。我们的假设是，IL-10是肥大细胞动态平衡的内源性介质。我们提出了明确的证据表明，IL-10抑制了鼠和人肥大细胞的功能和存活。初步的体内研究证实了这些数据。我们还表明，IL-10可能由两个来源提供：(I)激活的肥大细胞产生自分泌，(Ii)CD25+调节性T细胞(Treg)产生旁分泌。调控肥大细胞的动态平衡可能成为治疗炎症性疾病的有力工具。我们的具体目标是：1.确定IL-10在体外和体内如何抑制IgE受体的表达和功能。我们将检验以下假设：a.IL-10通过抑制Syk、Akt和Stat5的表达，利用Stat5抑制Fc？RI功能。在体内，IL-10抑制Fc？RI的表达，减轻IgE介导的过敏反应。IL-10由激活的肥大细胞和招募的Tregs提供。D.树突状细胞通过产生IL-10抑制体内肥大细胞的功能。研究IL-10在体内外对肥大细胞增殖和存活的抑制作用。我们将验证以下假设：A.IL-10通过抑制Stat5和Akt的表达而诱导肥大细胞周期停滞和凋亡。树突状细胞通过分泌IL-10抑制肥大细胞的增殖和存活。C.IL-10可能来源于Tregs，在体内抑制肥大细胞的增殖。

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.