Immune Regulation of Cysteinyl Leukotriene Biosynthesis

半胱氨酰白三烯生物合成的免疫调节

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：肥大细胞（MC）通过产生类二十烷酸，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，提供与支气管哮喘炎症过程的直接联系。除了具有激活MC的能力外，我们的初步研究现已表明，肽聚糖（PGN）是一种激活Toll样受体（TLR）-2的先天免疫刺激物，还可以诱导小鼠LTC4合酶（LTC4S）的表达骨髓来源的 MC（mBMMC）。用 PGN 启动 mBMMC 可提高其在离子载体刺激和 FceRI 交联后产生 LTC4 的能力。 LTC4S 表达也会被适应性免疫刺激物白细胞介素 (IL)-4 上调。此外，在 IL-4 存在的情况下，PGN 引发对 LTC4S 表达的影响会加性/协同增加。由于 cysLT 在支气管哮喘的发病机制中发挥着重要作用，因此我们的结果可以解释所观察到的微生物或病毒感染引起的哮喘恶化。由于TLR激活NF-κB而IL-4激活信号转导转录激活子(STAT)6，我们假设1)转录因子STAT6和NF-κB之间通过重叠来协同调节LTC4S基因的转录。 STAT6/NF-κB 位点，2) 微生物或病毒感染通过 TLR 信号通路激活先天免疫系统，通过增加细胞因子来加重支气管哮喘。 LTC4S 表达高于 IL-4 适应性免疫激活的最大效果。因此，我们提出以下具体目标： 1）研究各种TLR激动剂对其增加LTC4S表达的能力的影响，其与IL-4结合的影响以及NF-κB转录因子的作用； 2)确定mBMMC的IL-4和PGN引发加性增强LTC4S表达的机制； 3) 阐明体内IL-4和TLR信号传导对抗原攻击引起的肺部炎症反应以及过敏原诱导气道疾病的替代小鼠模型中乙酰甲胆碱气道反应性的协同作用。