Sphingosine-1-Phosphate, A Novel Mediator of Human Skin Mass Cell Functions

描述(由申请人提供)：对环境刺激过敏是特应性皮炎或湿疹表现出来的特应性的基本特征。肥大细胞广泛分布于皮肤，在特应性皮炎(AD)中肥大细胞数量增多。肥大细胞表面高亲和力IgE受体(FcepsilonRI)的抗原交联会导致肥大细胞脱颗粒，释放组胺和其他预形成的介质，以及几种促炎细胞因子和趋化因子。鞘氨醇代谢物-1-磷酸鞘氨醇(S1P)是肥大细胞活化后产生和释放的生物活性物质的新成员。FcepsilonRI激活SphK导致S1P的形成和分泌，S1P进而反式激活其受体S1P(1)和S1P(2)。S1P(1)是肥大细胞向抗原迁移的关键，S1P(2)是脱颗粒所必需的。这些信息来自对啮齿动物肥大细胞的研究，目前还不知道S1P在人类肥大细胞中的功能，特别是在皮肤过敏反应和皮肤病中的功能。我们认为，与啮齿动物肥大细胞类似，S1P是由FcepsilonRI激活SphKs进而激活S1PR而产生的，在人类皮肤肥大细胞的脱颗粒、细胞因子和趋化因子释放以及它们向炎症部位移动的过程中起着至关重要的作用。本应用的目的是：检测SphKs、S1P和S1P受体在脱颗粒和分泌趋化因子和细胞因子中的作用；阐明S1PR参与人肥大细胞向抗原运动；评价S1P参与人肥大细胞的生存和发育；最后，确定S1P是如何通过自分泌/旁分泌的方式传递信号的。AD是最常见的皮肤病之一，是一种慢性炎症性皮肤病，约占成年人口的2-3%，皮肤肥大细胞对G蛋白激活剂非常敏感，其分泌和应答S1P的能力表明，这种强大的脂质介质可能在正反馈环路中作用，加重和延长过敏性皮肤反应和特应性皮炎、接触性过敏和银屑病的发展。这些研究结果将加深我们对肥大细胞激活、募集和增殖的了解，并可能为开发针对S1P功能的新的治疗药物提供基础，以治疗特应性皮炎和湿疹等皮肤炎症性疾病。

DESCRIPTION (provided by applicant): Hypersensitivity to environmental stimuli is a fundamental feature of atopy that manifests itself through atopic dermatitis or eczema. Mast cells are distributed widely in the skin and increased in number in atopic dermatitis (AD). Antigen cross-linking of the high affinity receptor for IgE (FcepsilonRI) on mast cells causes their degranulation, release of histamine and other preformed mediators, as well as several proinflammatory cytokines and chemokines. The sphingolipid metabolite sphingosine-1-phosphate (S1P) is a new addition to the bioactive compounds produced and released by activated mast cells. FcepsilonRI triggering activates sphingosine kinase (SphK) leading to formation and secretion of S1P which in turn transactivates its receptors S1P(1) and S1P(2). S1P(1) is critical for migration of mast cells toward antigen and S1P(2) is required for degranulation. This information emerged from studies of rodent mast cells and nothing is yet known of the functions of S1P in human mast cells and particularly in skin allergic responses and dermatoses. We propose that, similar to rodent mast cells, S1P produced by activation of SphKs and consequently S1PRs by FcepsilonRI triggering plays a crucial role in human skin mast cell functions including degranulation, cytokine and chemokine release, and their movement to sites of inflammation. The objectives of this application are: to examine role of SphKs, S1P, and S1P receptors in degranulation and secretion of chemokines and cytokines; to elucidate the involvement of S1PRs in movement of human mast cells towards antigen; to evaluate the involvement of S1P in survival and development of human mast cells; and finally, to determine how S1P is transported out of human mast cells to signal in an autocrine/paracrine fashion. AD, one of the most common dermatoses, is a chronic inflammatory skin disease affecting about 2- 3% of the adult population, skin mast cells are very responsive to G protein activators and their ability to secrete and respond to S1P suggests that that this potent lipid mediator could act in positive feedback loop to aggravate and prolong the allergic cutaneous response and the development of atopic dermatitis, contact allergy and psoriasis. The results of the proposed studies will enhance our understanding of mast cell activation, recruitment and proliferation, and could provide the basis for development of new therapeutic agents targeting S1P functions to treat inflammatory disorders of skin, such as atopic dermatitis and eczema.