Cysteinyl leukotriene signaling in proliferation, cytokine production and PGD2 ge

增殖、细胞因子产生和 PGD2 基因中的半胱氨酰白三烯信号传导

• 批准号: 7788006
• 负责人: Sailaja Paruchuri
• 金额: $ 8.96万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7788006
• 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; cytokine; desensitization; human subject; in vivo; interest; leukotriene-C4 synthase; lipid mediator; mast cell; member; novel; public health relevance; receptor; receptor-mediated signaling; response; synthetic enzyme; treatment strategy; vascular inflammation

DESCRIPTION (provided by applicant): 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 PPAR3 or P2Y12 receptor abrogates LTE4-induced MIP-12 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 hypothesize that 1. Different PKCs mediate CysLTR-mediated responses and 2. LTE4 differs from its precursors by stimulating strong signaling through a PPAR-3-dependent mechanism and its responses involve contributions from CysLT1-like receptors, P2Y12 receptor and PPAR-3. 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. PUBLIC HEALTH RELEVANCE: This proposal seeks to determine how a common lipid mediator leukotriene E4 can regulate the activation of mast cells, important cells mediating the inflammatory responses in response to allergens and infectious agents. Studying this could help us in better understanding and treatment strategies for asthma and other allergies.

描述（由申请人提供）：Cys-LT 是有效的支气管收缩剂、血管渗漏的强大诱导剂和气道高反应性增强剂，在哮喘中发挥重要作用。 MC 作为效应细胞在哮喘中的重要性使得了解 cys-LT 调节 MC 功能的基本机制势在必行。 LTE4 虽然是最丰富和最稳定的 cys-LT，但它是已知 CysLTR 的弱部分激动剂，但会在体内诱导独特的反应，这是 LTC4 或 LTD4 无法重现的。我们的初步研究表明，LTE4 有效刺激 hMC 中的细胞增殖、细胞因子产生和 COX-2 依赖性 PGD2 生成，而传统 CysLTR 无法解释这一点。阻断 PPAR3 或 P2Y12 受体可消除 LTE4 诱导的 MIP-12 生成以及 LAD2 细胞中的 PGD2 反应。与此相称的是，与 LTD4 不同，LTE4 在致敏的 BALB/c 小鼠中会放大由低剂量过敏原诱导的粘膜炎症，而炎症是由 P2Y12 受体介导的。这表明，与普遍认为LTD4是cys-LT的主要效应器的观点相反，LTE4可能在粘膜和血管炎症中具有核心且独特的作用。在本次资助中，我们假设 1. 不同的 PKC 介导 CysLTR 介导的反应，2. LTE4 与其前体不同，它通过 PPAR-3 依赖性机制刺激强信号传导，其反应涉及 CysLT1 样受体、P2Y12 受体和 PPAR-3 的贡献。我们试图识别参与这些反应的信号中间体并分析对肥大细胞功能的影响。 cys-LT 和主要的 MC 衍生的类二十烷酸 (PGD2) 在人类哮喘病理学中含量丰富，都会诱导和放大小鼠实验性过敏性肺部炎症。尽管这些调解者类别参与相同的环境，但人们对它们之间的交叉监管知之甚少。 cys-LTs 在粘膜炎症中显着调节 MC 发育这一事实表明，局部衍生的 cys-LTs 可以通过作用于 MCs 来控制 PGD2 的产生。如果正确的话，这可能会对哮喘和过敏性疾病，特别是对 Th2 反应的控制产生重大的发病和治疗意义。 公共健康相关性：该提案旨在确定常见的脂质介质白三烯 E4 如何调节肥大细胞的激活，肥大细胞是介导针对过敏原和感染因子的炎症反应的重要细胞。研究这一点可以帮助我们更好地了解哮喘和其他过敏症并制定治疗策略。

项目成果

Cysteinyl leukotrienes regulate endothelial cell inflammatory and proliferative signals through CysLT₂ and CysLT₁ receptors.

• DOI: 10.1038/srep03274
• 发表时间: 2013-11-20
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Duah, Ernest;Adapala, Ravi K.;Al-Azzam, Nosayba;Kondeti, Vinay;Gombedza, Farai;Thodeti, Charles K.;Paruchuri, Sailaja
• 通讯作者: Paruchuri, Sailaja