Eicosanoids and lung macrophage antimicrobial mechanisms

类二十烷酸和肺巨噬细胞抗菌机制

基本信息

批准号：
7668216
负责人：
MARC L PETERS-GOLDEN
金额：
$ 38.3万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-07-10 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7668216
关键词：
1,2-diacylglycerol 1-Phosphatidylinositol 3-Kinase 1-Phosphatidylinositol 4-Kinase Abbreviations Address Adenylate Cyclase Alveolar Alveolar Macrophages Arachidonate 5-Lipoxygenase Arachidonic Acids Attention Binding Biological CREB1 gene Categories Cell surface Cells Characteristics Cholesterol Chromosomes Chromosomes, Human, Pair 10 Class Coupling Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic AMP-Responsive DNA-Binding Protein Cyclodextrins Data Development Diglycerides Dinoprostone Disease Distal Eicosanoid Receptor Eicosanoids Erythrocytes Event Family Fc Receptor Figs - dietary Fluorescence Resonance Energy Transfer Funding G-Protein-Coupled Receptors GTPase-Activating Proteins Guanine Nucleotide Exchange Factors Guanosine Guanosine Triphosphate Phosphohydrolases Health Host Defense Immune Immune response Immunoglobulin G Immunologics Infection Ingestion Inositol Phosphates LTB4R gene Leukotriene B4 Leukotriene D4 Leukotriene Receptor Leukotrienes Ligation Lung Mediating Membrane Microdomains Microbe Molecular Monomeric GTP-Binding Proteins Natural Immunity Organ PTEN gene Pathway interactions Pertussis Toxin Phagocytes Phagocytosis Phosphatidylinositol Phosphates Phosphatidylinositols Phospholipase C Phosphoric Monoester Hydrolases Phosphotransferases Process Prostaglandin-Endoperoxide Synthase Prostaglandins Protein Isoforms Protein Kinase C Proteins Rattus Receptor Signaling Regulation Role Second Messenger Systems Sheep Signal Pathway Signal Transduction Testing Tyrosine abstracting analog antimicrobial arachidonate citrate carrier clinically relevant cyclooxygenase 1 cyclooxygenase 2 cysteinyl leukotriene receptor cysteinyl-leukotriene human WFDC2 protein immune function inhibitor/antagonist insight killings lipid mediator macrophage neutrophil opsonin receptor phosphatidylinositol phosphate receptor rho second messenger small hairpin RNA

项目摘要

Project Summary/Abstract: Infections of the lung have a greater impact on global health than any other category of disease, and there is an urgent need to better understand antimicrobial defense of the lung. Alveolar macrophages (AMs) are the resident innate immune defenders of the distal lung, and the immunologic repertoire of these cells often differs substantially from that of other phagocytic cells. Among the substances elaborated during infection, lipid mediators derived from arachidonate (eicosanoids), including leukotrienes (LTs) B4 (LTB4) and D4 (LTD4) as well as prostaglandin E2 (PGE2), have emerged as important modulators of innate immune function. Eicosanoids act by ligating specific G protein-coupled receptors on the cell surface and initiating signaling events. We have shown that both LTBB4 (via B LT receptor 1 [BLT1]) and LTD4 (via cysteinyl LT receptor 1 [cysLT1]) promote, while PGE2 (via E prostanoid receptors 2 and 4 [EP2 and EP4]) inhibits, AM capacity for phagocytosis and killing of IgG-opsonized microbes. However, the intracellular mechanisms by which these eicosanoids act are incompletely understood. Although both LT classes promote innate immune functions in AMs, they act via distinct signaling pathways. Likewise, suppression of AM innate immune functions following ligation of EP2 and EP4 is mediated by distinct pathways. As development of pharmacologic agents targeting specific eicosanoid receptors is proceeding rapidly, it is important that the effects of such targeted therapies on antimicrobial defenses of the lung are understood. This project seeks to understand the mechanisms by which these eicosanoids influence key events in the AM signaling pathway triggered by the receptor for opsonic IgG ¿ the Fc? receptor (FcR). The central signaling events we will focus on are activation of: 1) phosphoinositide 3- kinase (PI3K)/phosphatase and tensin homolog deleted on chromosome 10 (PTEN); 2) isoforms of protein kinase C (PKC); and 3) small GTPases. The hypothesis is that divergent effects on these FcR-triggered signaling components by ligation of BLT1 vs. cysLT1 and EP2 vs. EP4 reflect the differential localization of these receptors to lipid raft membrane microdomains and their differential coupling to two distinct cyclic AMP effectors ¿ protein kinase A (PKA) and exchange protein activated by cyclic AMP (Epac-1). Employing primary rat AMs, we will address specific aims to determine: 1) regulation by PKA and Epac-1 of FcR-induced signaling events; 2) localization to lipid rafts of FcR and its downstream signaling components and the role of rafts in phagocytosis and killing; 3) the roles of PKA vs. Epac-1 and of lipid raft localization in explaining divergent modulation of FcR signaling by BLT1 vs. cysLT1 ligation; 4) the roles of PKA vs. Epac-1 and of lipid raft localization in explaining divergent modulation of FcR signaling by EP2 vs. EP4 ligation. These proposed studies will provide fundamental insights into AM antimicrobial function, and a clinically relevant framework for understanding and modulating innate immunity in the lung.

项目摘要/摘要：肺部感染对全球健康的影响比任何其他类别的疾病都更大，并且迫切需要更好地了解肺部的抗菌防御。肺泡巨噬细胞（AMS）居民是远端肺的先天免疫防御者，并且这些细胞的免疫学曲目经常与其他吞噬细胞不同。在感染过程中阐述的物质中源自蛛网膜（Eicosanoids）的脂质介质，包括白细胞（LTS）B4（LTB4）和D4（LTD4）以及前列腺素E2（PGE2）以及先天免疫功能的重要调节剂。类eicosanoids通过在细胞表面连接特定的G蛋白偶联受体并启动信号传导作用事件。我们已经表明LTBB4（通过B LT受体1 [BLT1]）和LTD4（通过Cysteinyl LT受体1 [Cyslt1]）促进，而PGE2（通过E前列腺素受体2和4 [EP2和EP4]）抑制AM的能力吞噬作用和IgG开放式微生物的杀戮。但是，这些细胞内机制类osanoids法案尚未完全理解。尽管这两个LT类都促进了先天免疫功能 AMS，它们通过不同的信号通路起作用。同样，抑制AM先天免疫功能之后 EP2和EP4的连接是由不同的途径介导的。作为靶向药理剂的开发特定的类素受体正在迅速进行，重要的是，这种靶向疗法对了解肺的抗菌防御能力。该项目旨在了解该项目的机制这些类固醇会影响接收器opsonic IgG触发的AM信号传导途径中的关键事件 FC？受体（FCR）。我们将重点关注的中心信号事件是激活：1）磷酸肌醇3-- 激酶（PI3K）/磷酸酶和Tensin同源物在10（PTEN）上删除； 2）蛋白质的同工型激酶C（PKC）; 3）小gtpase。假设是对这些FCR触发的不同影响通过BLT1与Cyslt1和EP2与EP4的连接来传导成分这些受体到脂质筏膜微区及其差异耦合到两个不同的环状AMP 效应子 - 蛋白激酶A（PKA）和通过环状AMP激活（EPAC-1）激活的蛋白质。雇用主要大鼠AMS，我们将解决确定的特定目的：1）通过PKA和EPAC-1对FCR诱导的信号传导进行调节事件； 2）定位于FCR的脂质筏及其下游信号传导成分以及筏在吞噬作用和杀戮； 3）PKA与EPAC-1和脂质筏定位的作用在解释不同通过BLT1与Cyslt1连接对FCR信号的调节； 4）PKA与EPAC-1和脂质筏的作用通过EP2与EP4连接解释FCR信号传导的分歧调制的定位。这些提议研究将提供对AM抗菌功能的基本见解，并为临床相关的框架理解和调节肺中的先天免疫力。