Cys-LT signaling in proliferation, cytokine production and PGD2 generation of MCs

MC 增殖、细胞因子产生和 PGD2 生成中的 Cys-LT 信号传导

基本信息

批准号：
8334594
负责人：
Sailaja Paruchuri
金额：
$ 24.88万
依托单位：
UNIVERSITY OF AKRON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-20 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8334594
关键词：
Adenosine Diphosphate Agonist Allergens Allergic Allergic Disease Animals Asthma Belief Binding Blood Vessels Breathing Bronchoalveolar Lavage Fluid Bronchoconstrictor Agents CREB1 gene Cell Proliferation Cell physiology Cells Chemosensitization Clinical Development Disease Dose Effector Cell Eicosanoids Extravasation Family Fibrosis G-Protein-Coupled Receptors Generations Grant Human Hypersensitivity In Vitro Inbred BALB C Mice Individual Infectious Agent Inflammatory Response Intranasal Administration Leukotriene C4 Leukotriene D4 Leukotriene E4 Ligands Mediating Mediator of activation protein Mucositis Mus PTGS2 gene Pathogenesis Pathology Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Pharmacology Phosphorylation Phosphotransferases Play Pneumonia Production Prostaglandin D2 Prostaglandins Protein Isoforms Protein Kinase C Regulation Role Sampling Signal Pathway Signal Transduction Source Testing Therapeutic Umbilical Cord Blood Urine activating transcription factor adaptive immunity airway hyperresponsiveness asthmatic patient chemokine clinical efficacy clopidogrel cysteinyl leukotriene receptor cysteinyl-leukotriene cytokine desensitization human subject in vivo interest leukotriene-C4 synthase lipid mediator mast cell member novel receptor receptor-mediated signaling response synthetic enzyme treatment strategy vascular inflammation

项目摘要

Cys-LTs are potent bronchoconstrictors, powerful inducers of vascular leakage and potentiators of airway hyperresponsiveness and play an essential role in asthma. The importance of MCs as effector cells in asthma makes it imperative to understand the basic mechanisms by which the cys-LTs regulate the function of MCs. LTE4, though the most abundant and stable of the cys-LTs, is a weak, partial agonist for the known CysLTRs, but induces unique responses in vivo that cannot be recapitulated by LTC4 or LTD4. Our preliminary Studies indicate that LTE4 potently stimulates cell proliferation, cytokine production, and COX-2-dependent PGD2 generation in hMCs that are not explained by the conventional CysLTRs. Blocking PPAR¿ or P2Y12 receptor abrogates LTE4-induced MIP-1¿ generation as well as PGD2 response in LAD2 cells. Complimenting this, in vivo LTE4 unlike LTD4 amplifies mucosal inflammation induced by low-dose allergen in sensitized BALB/c mice that is mediated by the P2Y12 receptor. This suggest that contrary to the widely held belief that LTD4 is the major effector cys- LT, LTE4 may have a central and unique role in mucosal and vascular inflammation. In the present grant, we hypothesise that 1. Different PKCs mediate CysLTR-mediated responses and 2. LTE4 differs from its precursors by stimulating strong signaling through a PPAR-¿-dependent mechanism and its responses involve contributions from CysLT1-like receptors, P2Y12 receptor and PPAR-¿. We attempt to identify signaling intermediates involved in these responses and analyze the effects on mast cell functions. Both cys-LTs and the major MC-derived eicosanoid, PGD2, are abundant in the pathology of asthma in humans both induce and amplify experimental allergic pulmonary inflammation in mice. Although these mediator classes participate in the same contexts, little is known regarding cross-regulation between them. The fact that cys-LTs prominently regulate MC development in mucosal inflammation suggests that locally-derived cys-LTs could control PGD2 production through actions on MCs. If correct, this could carry substantial pathogenetic and therapeutic implications for asthma and allergic diseases in particular and control of Th2 responses.

CYS-LT是潜在的支气管收集器，有力的血管泄漏影响者和气道高反应性的潜在者在哮喘中起着至关重要的作用。这 MC作为哮喘的效应细胞的重要性使得必须了解 CYS-LTS调节MC功能的基本机制。 lte4，虽然 CYS-LT的最丰富和稳定是已知的弱，部分激动剂 cysltrs，但影响了LTC4或无法概括的体内独特反应 LTD4。我们的初步研究表明，LTE4可能刺激细胞增殖，细胞因子的产生和COX-2依赖性PGD2在HMC中的生成不是由常规cysltrs解释。阻止PPAR或P2Y12受体废除 LTE4诱导的MIP-1引发以及LAD2细胞中的PGD2响应。称赞这一点，与LTD4放大器粘膜注入不同，体内LTE4诱导由P2Y12接收器介导的敏感BALB/C小鼠中的低剂量过敏原。这表明与广泛认为LTD4是主要效应器cys的信念形成鲜明对比。 LT，LTE4在粘膜和血管注射中可能具有中心和独特的作用。在目前的赠款，我们假设1。不同的PKC介导Cysltr介导的响应和2。LTE4通过刺激强信号传导与其前体不同通过PPAR-依赖性机制及其反应涉及的贡献 Cyslt1样受体，P2Y12受体和PPAR-。我们试图识别信号参与这些反应的中间体并分析对肥大细胞的影响功能。 CYS-LTS和主要MC衍生的eicosanoid PGD2在人类哮喘的病理既诱导又诱导实验过敏小鼠肺部炎症。尽管这些调解人课程参与相同的上下文，关于它们之间的交叉调节知之甚少。事实 CYS-LTS显着调节粘膜注射中MC的发育表明，本地衍生的CYS-LT可以通过对MC的动作来控制PGD2的生产。如果正确，这可能具有重大的致病性和治疗意义哮喘和过敏性疾病特别是对TH2反应的控制。