Immune Regulation of Cysteinyl Leukotriene Biosynthesis

半胱氨酰白三烯生物合成的免疫调节

• 批准号: 7571588
• 负责人: BING K LAM
• 金额: $ 41.5万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571588
• 关键词: Aerosols; Affinity; Agonist; Allergens; Anabolism; Animal Model; Asthma; Binding; Bone Marrow; Breathing; Consensus; Disease; Eicosanoids; Flare; Genes; Genetic Transcription; Human; IgE Receptors; Immune; Immune response; Immune system; Inbred BALB C Mice; Inflammatory; Inflammatory Response; Interleukin-4; Interleukins; Ionophores; Knockout Mice; Lead; Leukotriene C4; Link; Lung; Mediating; Mus; Nuclear; Pathogenesis; Pathway interactions; Peptidoglycan; Play; Pneumonia; Process; Prostaglandin D2; Prostaglandins; Proteins; Receptor Signaling; Regulation; Role; STAT protein; STAT6 Transcription Factor; STAT6 gene; Signal Pathway; Signal Transduction; Site; Stimulus; Therapeutic Agents; Toll-Like Receptor 2; Toll-like receptors; Umbilical Cord Blood; Virus Diseases; Wheat; Wild Type Mouse; airway hyperresponsiveness; airway inflammation; antigen challenge; crosslink; cysteinyl-leukotriene; cytokine; in vivo; intradermal injection; leukotriene D4 receptor; leukotriene-C4 synthase; mast cell; methacholine; microbial; mouse model; response; transcription factor

DESCRIPTION (provided by applicant): Mast cells (MCs) respond to activation by innate stimuli or cross linking of the high-affinity receptor for IgE (FceRI) by generating eicosanoids, particularly the cysteinyl leukotrienes (cysLTs) and prostaglandin (PG) D2, providing a direct link to the inflammatory processes in bronchial asthma. In addition to its ability to activate MC, our preliminary studies have now revealed that peptidoglycan (PGN), an innate immune stimulus which activates toll-like receptor (TLR)-2, can also induce the expression of LTC4 synthase (LTC4S) by mouse bone marrow-derived MCs (mBMMCs). Priming of mBMMCs with PGN increases their capacity to generate LTC4 upon ionophore stimulation and upon cross-linking of FceRI. LTC4S expression is also upregulated by an adaptive immune stimulus, interleukin (IL)-4. Moreover, the effect of PGN priming on LTC4S expression is additively/synergistically increased in the presence of IL-4. Because cysLTs play an important role in the pathogenesis of bronchial asthma, our results may explain the observed exacerbation of asthma by microbial or viral infection. Because TLR activates NF-?B and IL-4 activates signal transducer activator of transcription (STAT) 6, we hypothesize that 1) there is cooperation between the transcription factors STAT6 and NF-?B in regulating the transcription of LTC4S gene through the overlapping STAT6/NF-?B site(s), and 2) that activation of innate immune system by microbial or viral infections by TLR signaling pathways, aggravates bronchial asthma through an increase in cellular LTC4S expression above the maximal effect of adaptive immune activation by IL-4. We therefore propose the following Specific Aims: 1) To examine the effect of various TLR agonists on their ability to increase LTC4S expression, their effect in combination with IL-4 and the role of NF-?B transcription factor; 2) To determine the mechanism of additive enhancement of LTC4S expression by IL-4 and PGN priming of mBMMC; and 3) To elucidate synergistic effects of IL-4 and TLR signaling in vivo on the pulmonary inflammatory response to antigen challenge and on airway reactivity to methacholine in surrogate mouse models of allergen induced airway disease.

描述（由申请方提供）：肥大细胞（MC）通过产生类花生酸（特别是半胱氨酰白三烯（cysLT）和前列腺素（PG）D2）对先天刺激或IgE高亲和力受体（FceRI）交联的激活做出反应，从而与支气管哮喘的炎症过程直接相关。除了激活MC的能力外，我们的初步研究发现肽聚糖（PGN），一种激活Toll样受体（TLR）-2的先天性免疫刺激物，也可以诱导小鼠骨髓来源的MC（mBMMC）表达LTC 4合酶（LTC 4S）。用PGN引发mBMMC增加了它们在离子载体刺激和FceRI交联后产生LTC 4的能力。LTC 4S表达也被适应性免疫刺激物白细胞介素（IL）-4上调。此外，PGN引发对LTC 4S表达的作用在IL-4存在下是相加/协同增加的。由于cysLTs在支气管哮喘的发病机制中起着重要作用，我们的研究结果可以解释所观察到的微生物或病毒感染引起的哮喘加重。因为TLR激活NF-？B和IL-4激活信号转导转录激活因子（STAT 6），我们推测：1）转录因子STAT 6和NF-κ B之间存在协同作用; B通过STAT 6/NF-？B位点，和2）通过TLR信号传导途径由微生物或病毒感染激活先天免疫系统，通过细胞LTC 4 S表达的增加超过IL-4的适应性免疫激活的最大效应来缓解支气管哮喘。因此，我们提出了以下具体目的：1）检查各种TLR激动剂对它们增加LTC 4S表达的能力的影响，它们与IL-4组合的效果以及NF-？B转录因子; 2）确定mBMMC的IL-4和PGN引发的LTC 4S表达的加性增强的机制;和3）阐明IL-4和TLR信号传导在体内对抗原攻击的肺部炎症反应和过敏原诱导的气道疾病的替代小鼠模型中对乙酰甲胆碱的气道反应性的协同作用。