Role of PGE2 in Human Mast Cell Biology

肥大细胞(MC)启动过敏反应，参与抵抗感染的先天保护。通过高亲和力的Fc IgE受体(FcsRI)激活MC，诱导两种主要的二十烷类化合物的从头合成：由5-脂氧合酶/白三烯C4合成酶(5-LO/LTC4S)途径形成的半胱氨酰白三烯(CysLTS)和前列腺素(PG)D2，即PGH合成酶(PGHS)/PGD合成酶途径的产物。在体内，CysLTs和PGD2都通过特定的受体系统发挥作用，介导MC依赖的支气管收缩、白细胞募集和呼吸道高反应性。另一种二十烷类化合物PGE21对过敏性哮喘和阿司匹林耐受哮喘(AIA)都有明显的支气管保护作用。目前的初步数据显示，脐带血来源的人单核细胞(HMCs)对Toll样受体(TLR)2的配体葡萄球菌多肽(PGN)和TLR3的配体PolyI：C的刺激有反应，并延迟、持续地分泌PGE2。PGN诱导PGHS-2和微粒体PGE2合成酶-1(M-PGES-1)的mRNA及其相应蛋白的表达。值得注意的是，外源PGE2显著抑制HMCS产生cysLT和PGD2，并显著 抑制肿瘤坏死因子(TNF-a)和IL-5的产生 用PGN进行交联化或刺激。我们假设：1.先天性和获得性免疫反应引起MC产生二十烷类化合物的不同特征，其中PGHS-2和M-PGES-1均可诱导；2.PGE-通过一个以上的EP受体，以自分泌或旁分泌的方式限制MC激活的后果；以及3.AIA涉及可诱导的PGE2合成酶功能的失调。因此，我们提出了以下具体目标：1)确定通过不同跨膜刺激激活的HMCs持续合成PGE2的末端合成酶；2)确定PGE2介导的抑制HMC激活的受体和生化机制；3)确定AIA是否存在可诱导的PGE2合成系统缺陷。

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.