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

描述（由申请人提供）：对环境刺激的过敏是特应性的一个基本特征，表现为特应性皮炎或湿疹。肥大细胞广泛分布于皮肤，在特应性皮炎（AD）中肥大细胞数量增加。肥大细胞上IgE高亲和受体（FcepsilonRI）的抗原交联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。鞘脂代谢产物鞘鞘醇-1-磷酸（S1P）是肥大细胞活化后产生和释放的一种新的生物活性化合物。FcepsilonRI触发激活鞘氨酸激酶（SphK），导致S1P的形成和分泌，进而激活其受体S1P(1)和S1P(2)。S1P(1)是肥大细胞向抗原迁移的关键，而S1P(2)是脱颗粒所必需的。这一信息来自对啮齿动物肥大细胞的研究，但对于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，目前还一无所知。我们认为，与啮齿动物肥大细胞类似，FcepsilonRI触发SphKs和s1pr激活产生的S1P在人类皮肤肥大细胞功能中起着至关重要的作用，包括脱颗粒、细胞因子和趋化因子的释放，以及它们向炎症部位的移动。本应用程序的目的是：检查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S1PRs在人肥大细胞向抗原运动中的作用；评估S1P在人肥大细胞存活和发育中的作用；最后，确定S1P如何以自分泌/旁分泌的方式从人类肥大细胞转运到信号。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，皮肤肥大细胞对G蛋白激活剂非常敏感，其分泌和响应S1P的能力表明，这种有效的脂质介质可能在正反馈回路中加重和延长皮肤过敏性反应，并导致特应性皮炎、接触性过敏和牛皮癣的发生。这些研究结果将加深我们对肥大细胞活化、募集和增殖的理解，并为开发靶向S1P功能的新药物治疗皮肤炎症性疾病（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.