Role of PGE2 in Human Mast Cell Biology

PGE2 在人类肥大细胞生物学中的作用

基本信息

批准号：
7422408
负责人：
Joshua A Boyce
金额：
$ 50.94万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7422408
关键词：
1-Phosphatidylinositol 3-Kinase 5&apos Untranslated Regions Abbreviations Adenosine Affinity Allergens Allergic Antibodies Arachidonate 5-Lipoxygenase Aspirin Asthma Biochemical Bone Marrow Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid CREB1 gene Carboxypeptidase A Cellular biology Chromatography Chymase Cyclic AMP Cyclic AMP Response Element Cyclic AMP-Dependent Protein Kinases Cyclic AMP-Responsive DNA-Binding Protein Cyclosporine Cytosolic Phospholipase A2 Data Defect Dinoprostone Disease Eicosanoids Elements Enzymes Extracellular Signal Regulated Kinases Fc Receptor Functional disorder G-Protein-Coupled Receptors Generations Green Fluorescent Proteins Growth HTATIP gene Hematopoietic Human IgE Receptors Immune response Immunoglobulins In Vitro Infection Inflammatory Interleukin-4 Interleukin-5 Interleukins Irrigation Leukocytes Leukotriene C4 Leukotrienes Ligands Lipopolysaccharides Liquid substance MAP Kinase Gene MEKs Macrophage Inflammatory Proteins Mediating Mitogen-Activated Protein Kinases Mitogens Mus NF-AT NF-kappa B Natural Immunity Nuclear Numbers PLA2G4A gene PTGS2 gene Parents Pathogenesis Pathway interactions Patients Peptidoglycan Pertussis Toxin Phase Phospholipase A2 Phosphotransferases Physiological Play Poly I-C Polymerase Chain Reaction Production Prostaglandin D2 Prostaglandin E Receptor Prostaglandin-Endoperoxide Synthase Prostaglandins Prostaglandins E Prostaglandins H Proteins Pulmonary Function Test/Forced Expiratory Volume 1 Reaction Recombinants Reverse Transcription Role Signal Transduction Single Nucleotide Polymorphism Small Interfering RNA Source Stem Cell Factor Stimulus System TLR3 gene TNF gene Thromboxane A2 Receptor Tissues Toll-Like Receptor 2 Toll-like receptors Tumor Necrosis Factor-alpha Tumor Necrosis Factors Umbilical Cord Blood Untranslated Regions Uridine Uridine Diphosphate Variant activating transcription factor airway hyperresponsiveness autocrine cell type cyclooxygenase 1 cyclooxygenase 2 cysteinyl leukotriene receptor 2 cysteinyl-leukotriene cytokine extracellular human PLA2G4A protein human TNF protein in vivo leukotriene-C4 synthase mast cell progenitor programs prostaglandin D receptor prostaglandin R2 D-isomerase protein phosphatase inhibitor-2 receptor response tumor necrosis factor receptor superfamily, member 10b protein, mouse

项目摘要

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.

肥大细胞 (MC) 会引发过敏反应，并参与对感染的先天保护。通过 IgE 高亲和力 Fc 受体 (FcsRI) 激活 MC，诱导两种主要类二十烷酸从头合成：由 5-脂氧合酶/白三烯 C4 合酶 (5-LO/LTC4S) 途径形成的半胱氨酰白三烯 (cysLT) 和前列腺素(PG) D2，PGH 合酶 (PGHS)/PGD 合酶途径序列的产物。 cysLT 和 PGD2 均通过特定受体系统发挥作用，介导体内 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 PGE21 对过敏性哮喘和阿司匹林不耐受性哮喘 (AIA) 具有显着的支气管保护作用。初步数据显示，脐带血来源的人类 MC (hMC) 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，延迟，持续分泌PGE2。 PGN 诱导 PGHS-2 和微粒体 PGE2 合酶-1 (M-PGES-1) 的 mRNA 以及相应蛋白质的表达。值得注意的是，外源性 PGE2 显着抑制 hMC 产生 cysLT 和 PGD2，并且显着抑制抑制肿瘤坏死因子 (TNF-a) 和 IL-5 的产生，以响应 FcsRI 交联或用 PGN 刺激。我们假设 1. 先天性和适应性免疫反应引起 MC 产生类二十烷酸的不同特征，其中 PGHS-2 和 M-PGES-1 在每种反应中均可诱导； 2. PGE&通过一种以上的EP受体，以自分泌或旁分泌的方式限制MC激活的后果； 3. AIA 涉及诱导型 PGE2 合酶功能失调。因此，我们提出以下具体目标：1) 定义负责通过不同跨膜刺激激活的 hMC 中 PGE2 合成持续阶段的末端合酶，2) 定义负责 PGE2 介导的 hMC 激活抑制的受体和生化机制， 3) 确定诱导型 PGE2 合成系统的缺陷是否是 AIA 的基础。