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

Cys-Lts是强有力的支气管收缩药，强有力的血管渗漏诱导剂和 它是呼吸道高反应性的增强剂，在哮喘中起着重要作用。这个 巨噬细胞作为效应细胞在哮喘中的重要性使得了解 Cys-Lts调节MC功能的基本机制。LTE4，尽管 在Cys-Lts中含量最丰富和最稳定的是已知的弱的部分激动剂 CysLTRs，但在体内诱导独特的反应，不能用LTC4或 LTD4。我们的初步研究表明，LTE4有效地刺激细胞增殖， HMCs细胞因子的产生和COX-2依赖的PGD2的产生 由传统的CysLTRs解释。阻断PPAR或P2Y12受体的作用 LTE4诱导LAD2细胞产生MIP-1和PGD2反应。 值得称赞的是，与LTD4不同的是，在体内LTE4可以放大由LTD4引起的粘膜炎症 通过P2Y12受体介导的致敏BALB/c小鼠的低剂量变应原。 这表明，与LTD4是主要效应者的普遍看法相反，CyS- LT、LTE4可能在粘膜和血管炎症中起着中心和独特的作用。在……里面 目前的拨款，我们假设：1.不同的PKC介导的CysLTR 反应和2.LTE4不同于它的前体，它刺激强烈的信号 通过依赖于PPAR的机制，其反应涉及来自 CysLT1样受体、P2Y12受体和PPAR-β。我们试图识别信号 并分析其对肥大细胞的影响 功能。Cys-Lts和主要的MC来源的二十烷类化合物PGD2都含有丰富的 人类哮喘的病理机制既能诱发并放大实验性过敏 小鼠肺部炎症。尽管这些中介类参与了 在同样的背景下，人们对它们之间的交叉监管知之甚少。事实是， 半胱氨酸氨基转移酶显著调节黏膜炎症MC的发展 局部来源的Cys-Lts可通过作用于MC来调控PGD2的产生。如果 正确，这可能具有实质性的致病和治疗意义 哮喘和过敏性疾病，特别是Th2反应的控制。

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.