Regulation of Mast Cell Homeostasis by Interleukin-10

肥大细胞是过敏反应中最具特征的效应细胞之一。肥大细胞效应器功能现在不仅与过敏性疾病有关， 哮喘，而且关节炎，多发性硬化症和冠状动脉疾病。因此，了解肥大细胞的发育、功能和存活具有临床意义。我们的实验室一直在研究马槟榔碱介导的调节肥大细胞生物学作为免疫稳态的模型。在这方面，我们已经发现IL-10是肥大细胞稳态的多功能调节剂。白细胞介素（IL）-10是一种有效的调节性细胞因子，参与Th 1和Th 2免疫应答，与炎症性疾病如多发性硬化症、系统性红斑狼疮和克罗恩病密切相关。 使用IL-10信号传导作为模型系统，本申请将评估Th 2细胞因子对肥大细胞发育、功能和存活的稳态作用。我们的具体目标是： I.探讨IL-10诱导肥大祖细胞凋亡的机制 二.确定IL-10改变肥大细胞功能的机制。 III.确定IL-10+IL-4共刺激诱导培养的肥大细胞的细胞周期阻滞和凋亡的机制 这些目标集中于转录因子Stat 3在IL-10信号传导中的作用，并将采用原代骨髓来源的肥大细胞群作为测定系统。该提案的目标将通过标准的组织培养和分子生物学方法来实现，通过对IL-10调节的肥大细胞呼叫转录组和Stat 3在该基因调节中的作用的寡核苷酸微阵列分析来增强。完成后，这些研究将提供一个更完整的了解免疫稳态和作用的Th 2细胞因子在这一过程中。虽然这些研究与过敏性疾病有直接关系，但它们将影响我们对多发性硬化症、关节炎和心血管疾病等炎症性疾病的理解。

Mast cells are one of the best-characterized effectors in the allergic response. Mast cell effector functions are now being tied not only to allergic diseases such as asthma, but also to arthritis, multiple sclerosis, and coronary artery disease. Thus, understanding mast call development, function, and survival is clinically significant. Our laboratory has been investigating cytokine-mediated regulation of mast cell biology as a model of immune homeostasis. In this regard, we have found IL-10 to be a multi-functional regulator of mast cell homeostasis. Intedeukin (IL)-10 is a potent regulatory cytokine involved in the Th1 and Th2 immune responses, with close ties to inflammatory diseases such as multiple sclerosis, systemic lupus erythematosus and Crohn's disease. Using IL-10 signaling as a model system, this application will assess the homeostatic effects of Th2 cytokines on mast cell development, function, and survival. Our Specific Aims are: I. To determine the mechanism by which IL-10 induces apoptosis of developing mast cell progenitors II. To determine the mechanism by which IL-10 alters mast cell function II1. III.To determine the mechanism by which co-stimulation with IL-10+IL-4 induces cell cycle arrest and apoptosis of cultured mast cells These aims focus on the role of the transcription factor Stat3 in IL-10 signaling, and will employ primary bone marow-derived mast call populations as an assay system. The goals of this proposal will be accomplished by standard tissue culture and molecular biology approaches, augmented by oligonucleotide microarray analyses of the IL-10-regulated mast call transcriptome and the role of Stat3 in this gene regulation. When completed, these studies will offer a more complete understanding of immune homeostasis and the role Th2 cytokines have in this process. Though most directly related to allergic disease, these studies will impact our understanding of inflammatory diseases such as multiple sclerosis, arthritis, and cardiovascular disease.