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: 7258510
• 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/7258510
• 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（由申请人提供）：肥大细胞（MCs）通过产生类二十烷，特别是半胱氨酸白三烯（cysLTs）和前列腺素（PG） D2，对先天刺激或IgE高亲和受体（FceRI）交联的激活作出反应，与支气管哮喘的炎症过程直接相关。除了能够激活MC外，我们的初步研究现在已经揭示了肽聚糖（PGN），一种激活toll样受体(TLR)-2的先天免疫刺激，也可以诱导小鼠骨髓源性MCs （mBMMCs）表达LTC4合成酶（LTC4S）。用PGN启动mbmcs可以增加它们在离子团刺激和FceRI交联时产生LTC4的能力。LTC4S的表达也可通过适应性免疫刺激白介素-4上调。此外，在IL-4的存在下，PGN启动对LTC4S表达的影响会增加/协同增加。由于cylts在支气管哮喘的发病机制中起重要作用，我们的研究结果可以解释微生物或病毒感染导致哮喘恶化的现象。因为TLR激活了NF-？B和IL-4激活转录信号转导激活因子（STAT） 6，我们假设1)转录因子STAT6和NF-？B通过STAT6/NF-?重叠调控LTC4S基因的转录B位点(s)，以及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LTC4S表达而加重支气管哮喘，超过IL-4适应性免疫激活的最大作用。因此，我们提出以下具体目的：1)检测各种TLR激动剂对其增加LTC4S表达能力的影响，它们与IL-4的联合作用以及NF-？B转录因子；2)确定IL-4和PGN对mBMMC加性增强LTC4S表达的作用机制；3)阐明IL-4和TLR信号在体内对抗原攻击的肺部炎症反应和对甲胆碱的气道反应性的协同作用。