Role of PGE2 in Human Mast Cell Biology

肥大细胞（MC）启动过敏反应，并参与先天性保护免受感染。通过IgE的高亲和力Fc受体（Fc ε RI）的MC活化诱导两种主要类花生酸的从头合成：半胱氨酰白三烯（cysLT），其由5-脂氧合酶/白三烯C4合酶（5-LO/LTC 4S）途径形成，和前列腺素（PG）D2，其为PGH合酶（PGHS）/PGD合酶途径序列的产物。cysLT和PGD 2通过特异性受体系统介导MC依赖性支气管收缩、白细胞募集和体内气道高反应性。另一种类二十烷酸，PGE 21在过敏性和阿司匹林不耐受性哮喘（AIA）中具有显著的支气管保护作用。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poly I：C（TLR 3的配体）的刺激有反应，并具有延迟的持续PGE 2分泌。PGN诱导PGHS-2和微粒体PGE 2合酶-1（M-PGES-1）的mRNA表达，沿着相应的蛋白。值得注意的是，外源性PGE 2显著抑制hMC产生cysLT和PGD 2，并且显著抑制hMC产生cysLT和PGD 2。 抑制肿瘤坏死因子（TNF-α）和IL-5的产生， 与PGN交联或刺激。我们假设1。先天性和适应性免疫应答引起来自MC的类花生酸生成的对比谱，其中PGHS-2和M-PGES-1在每种中是可诱导的; 2. PGE&通过一个以上的EP受体，限制MC激活的后果，自分泌或旁分泌的方式;和3。AIA涉及诱导型PGE 2合酶功能失调。因此，我们提出了以下具体目标：1）确定负责通过不同跨膜刺激激活的hMC中PGE 2合成持续阶段的末端转移酶，2）确定负责PGE 2介导的hMC激活抑制的受体和生化机制，以及3）确定诱导型PGE 2合成系统中的缺陷是否是AIA的基础。

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.