IL-10 Regulates Mast Cell Function and Survival

描述（由申请人提供）：我们的建议将调查临床上重要的领域肥大细胞稳态。肥大细胞因其在过敏和哮喘中的作用而闻名，并且最近被认为与炎症性疾病如多发性硬化症、关节炎和心脏病有关。对炎症性疾病的理解中的一个关键差距是肥大细胞反应通常如何被抑制以防止慢性炎症。我们的假设是IL-10是肥大细胞稳态的内源性介质。我们提出了明确的证据表明，IL-10抑制小鼠和人类肥大细胞的功能和生存。初步的体内研究证实了这些数据。我们还表明，IL-10可能由两种来源提供：（I）活化肥大细胞的自分泌产物，和（II）CD 25+调节性T细胞（Treg）的旁分泌产物。操纵肥大细胞内稳态可能是治疗炎症性疾病的有力工具。我们的具体目标是：一。确定IL-10如何在体外和体内抑制IgE受体表达和功能。我们将测试以下假设：A。IL-10利用Stat 5抑制Fc？RI通过抑制Syk、Akt和Stat 5的表达发挥作用。B。IL-10抑制Fc？RI表达，并减轻IgE介导的过敏反应。C. IL-10由活化的肥大细胞和募集的T细胞提供。D.甲状腺激素通过产生IL-10抑制肥大细胞的体内功能。二.确定IL-10如何在体外和体内抑制肥大细胞增殖和存活。我们将测试以下假设：A。IL-10通过抑制Stat 5和Akt的表达诱导肥大细胞的细胞周期阻滞和凋亡。B。胸腺肽通过分泌IL-10抑制肥大细胞增殖和存活。C. IL-10，可能来源于TGF 1 α，在体内抑制肥大细胞增生。

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.