Role of PGE2 in Human Mast Cell Biology

肥大细胞（MCs）启动过敏反应，并参与先天保护免受感染。MC通过高亲和的IgE Fc受体（FcsRI）激活，诱导两种主要的20烷类化合物的重新合成：半胱氨酸白三烯（cyyslts），由5-脂氧合酶/白三烯C4合成酶{5-LO/LTC4S)途径形成，以及前列腺素（PG） D2， PGH合成酶(PGHS)/PGD合成酶途径序列的产物。cysLTs和PGD2均通过特异性受体系统在体内介导mc依赖性支气管收缩、白细胞募集和气道高反应性。另一种类二十烷酸PGE2l在过敏性哮喘和阿司匹林不耐受哮喘（AIA）中均具有明显的支气管保护作用。目前的初步数据显示，脐带血来源的人MCs （hMCs）对葡萄球菌肽聚糖（PGN） （toll样受体（TLR） 2的配体）和聚I:C （TLR3的配体）的刺激有反应，PGE2的分泌延迟，持续。PGN诱导PGHS-2和微粒体PGE2合成酶-1 (M-PGES-1) mrna以及相应蛋白的表达。值得注意的是，外源性PGE2显著抑制hmc生成cysLT和PGD2

Mast cells (MCs) initiate allergic responses and are involved in innate protection from infections. MC activation through the high-affinity Fc receptor for IgE (FcsRI) induces de novo synthesis of two major eicosanoids: cysteinyl leukotrienes (cysLTs), formed by the 5-lipoxygenase/leukotriene C4 synthase {5-LO/LTC4S) pathway, and prostaglandin (PG) D2, a product of the PGH synthase (PGHS)/PGD synthase pathway sequence. Both cysLTs and PGD2 act through specific receptor systems to mediate MC-dependent bronchconstriction, leukocyte recruitment, and airway hyperresponsiveness in vivo. Another eicosanoid, PGE2l is markedly bronchoprotective in both allergic and aspirin-intolerant asthma (AIA). Preliminary data now reveal that cord blood-derived human MCs (hMCs) respond to stimulation with staphylococcal peptidoglyan (PGN), a ligand for toll-like receptor (TLR) 2, and to poly I:C, a ligand for TLR3, with delayed, sustained secretion of PGE2. PGN induces expression of mRNAfor both PGHS-2 and microsomal PGE2 synthase-1 (M-PGES-1), along with the corresponding proteins. Notably, exogenous PGE2 markedly inhibits cysLT and PGD2 generation by hMCs, and substantially inhibits the production of tumor necrosis factor (TNF-a) and IL-5 in response to either FcsRI crosslinkage or stimulation with PGN. We hypothesize that 1. Innate and adaptive immune responses elicit contrasting profiles of eicosanoid generation from MCs, with PGHS-2 and M-PGES-1 being inducible in each; 2. PGE& through more than one EP receptor, limits consequences of MC activation in an autocrine orparacrine manner; and 3. AIA involves dysregulation of inducible PGE2 synthase function. We therefore propose the following Specific Aims: 1) to define the terminal synthases responsible for the sustained phase of PGE2 synthesis in hMCs activated through different transmembrane stimuli, 2) to define the receptors and biochemical mechanisms responsible for PGE2-mediated inhibition of hMC activation, and 3) to determine whether defects in the inducible PGE2 synthesis system underlie AIA.