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

描述（由申请人提供）：对环境刺激的超敏反应是特应性的一个基本特征，通过特应性皮炎或湿疹表现出来。肥大细胞广泛分布于皮肤中，并且在特应性皮炎（AD）中数量增加。肥大细胞上IgE的高亲和力受体（Fc ε RI）的抗原交联导致其脱粒、组胺和其他预先形成的介质以及几种促炎细胞因子和趋化因子的释放。鞘脂代谢物鞘氨醇-1-磷酸（S1 P）是一种新的除了生物活性化合物产生和释放的活化肥大细胞。FcepsilonRI触发激活鞘氨醇激酶（SphK），导致S1 P的形成和分泌，进而反式激活其受体S1 P（1）和S1 P（2）。S1 P（1）是肥大细胞向抗原迁移的关键，而S1 P（2）是脱粒所必需的。这一信息来自啮齿动物肥大细胞的研究，而S1 P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尚不清楚。我们认为，与啮齿类动物肥大细胞相似，通过激活SphKs产生的S1 P以及随后通过FcepsilonRI触发的S1 PRs在人类皮肤肥大细胞功能中起着至关重要的作用，包括脱粒、细胞因子和趋化因子释放以及它们向炎症部位的移动。本申请的目的是：检测SphKs、S1 P和S1 P受体在趋化因子和细胞因子的脱粒和分泌中的作用;阐明S1 PR参与人肥大细胞向抗原的运动;评价S1 P参与人肥大细胞的存活和发育;最后，确定S1 P如何从人肥大细胞中转运出来，以自分泌/旁分泌方式发出信号。AD是最常见的皮肤病之一，是一种慢性炎症性皮肤病，影响约2- 3%的成年人群，皮肤肥大细胞对G蛋白激活剂非常敏感，它们分泌和响应S1 P的能力表明这种有效的脂质介质可以在正反馈回路中起作用，以加重和延长过敏性皮肤反应和特应性皮炎的发展，接触性过敏和牛皮癣。拟议的研究结果将增强我们对肥大细胞活化、募集和增殖的理解，并可能为开发靶向S1 P功能的新治疗药物以治疗皮肤炎性疾病（如特应性皮炎和湿疹）提供基础。

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.