Cysteinyl leukotriene signaling in proliferation, cytokine production and PGD2 ge

描述（由申请人提供）：Cys-LT是强效支气管收缩剂、血管渗漏的强效诱导剂和气道高反应性的增强剂，在哮喘中起重要作用。MC作为效应细胞在哮喘中的重要性使得理解cys-LTs调节MC功能的基本机制成为必要。尽管LTE 4是最丰富和最稳定的cys-LT，但它是已知CysLTR的弱的部分激动剂，但在体内诱导的独特反应不能被LTC 4或LTD 4重现。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依赖的PGD 2在hMCs的传统的CysLTR不能解释的生成。阻断PPAR 3或P2 Y12受体可消除LAD 2细胞中LTE 4诱导的MIP-12生成以及PGD 2反应。补充这一点，在体内LTE 4不像LTD 4放大粘膜炎症诱导的低剂量过敏原在致敏的BALB/c小鼠，这是由P2 Y12受体介导的。这表明，与LTD 4是主要效应物cys-LT的普遍观点相反，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介导的反应和2。LTE 4与其前体的不同之处在于通过PPAR-3依赖性机制刺激强信号传导，其反应涉及CysLT 1样受体、P2 Y12受体和PPAR-3的贡献。我们试图确定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衍生的类花生酸PGD 2在人类哮喘的病理学中是丰富的，它们都诱导和放大小鼠的实验性过敏性肺部炎症。虽然这些中介类参与在相同的上下文中，很少有人知道它们之间的交叉调节。cys-LT在粘膜炎症中显著调节MC发育的事实表明，局部来源的cys-LT可以通过对MC的作用来控制PGD 2的产生。如果正确的话，这可能对哮喘和过敏性疾病，特别是对Th 2应答的控制，具有重要的致病和治疗意义。 公共卫生相关性：该提案旨在确定一种常见的脂质介质白三烯E4如何调节肥大细胞的活化，肥大细胞是介导过敏原和感染因子引起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的治疗策略。

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.