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

• 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
• 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

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是有效的支气管收缩剂，血管渗漏的强力诱导剂， 气道高反应性的增强剂，并在哮喘中发挥重要作用。的 MC作为效应细胞在哮喘中的重要性使得了解其在哮喘中的作用至关重要。 cys-LTs调控MCs功能的基本机制。LTE 4虽然 最丰富和稳定的cys-LT，是一个弱的，部分激动剂的已知 CysLTR，但在体内诱导独特的反应，不能被LTC 4或 LTD4.我们的初步研究表明，LTE 4有效地刺激细胞增殖， 细胞因子的产生和考克斯-2依赖性PGD 2的产生， 由常规CysLTR解释。阻断PPAR γ或P2 Y12受体 LTE 4诱导的MIP-1？生成以及LAD 2细胞中的PGD 2应答。 补充这一点，在体内LTE 4不像LTD 4放大粘膜炎症诱导 在致敏BALB/c小鼠中，低剂量变应原通过P2 Y12受体介导。 这表明，与广泛认为LTD 4是主要效应子cys- LT、LTE 4可能在粘膜和血管炎症中具有中心和独特的作用。在 目前的补助金，我们假设，1。不同的PKC介导CysLTR介导的 答案和2。LTE 4与其前体的不同之处在于刺激强烈的信号传导 通过一个依赖于过氧化物酶体增殖物激活受体的机制，其反应涉及 CysLT 1样受体、P2 Y12受体和PPAR-γ。我们试图识别信号 中间体参与这些反应，并分析对肥大细胞的影响 功能协调发展的cys-LT和主要的MC衍生的类花生酸PGD 2都丰富于 人类哮喘病理学既诱导又放大了实验性变态反应 小鼠肺部炎症。虽然这些中介类参与了 在相同的背景下，对它们之间的交叉调节知之甚少。的事实 cys-LT显著调节粘膜炎症中MC的发育，表明 局部来源的cys-LT可以通过作用于MC来控制PGD 2的产生。如果 正确的，这可能会带来实质性的致病和治疗影响， 特别是哮喘和过敏性疾病以及控制Th 2应答。