EFFECT OF INTERLEUKIN 5 RECEPTOR ACTIVATION ON EOSINOPHIL SIGNAL TRANSDUCTION

白细胞介素 5 受体激活对嗜酸性粒细胞信号转导的影响

• 批准号: 6410556
• 负责人: PAUL JOHN BERTICS
• 金额: $ 19.62万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6410556
• 关键词: antiport; apoptosis; asthma; cell adhesion; chemotaxis; cytokine receptors; enzyme activity; eosinophil; human tissue; immunoregulation; inflammation; integrins; interleukin 5; leukotrienes; mitogen activated protein kinase; phosphorylation; receptor binding; receptor expression; tissue /cell culture; transcription factor

Allergic inflammation and asthma are characterized by eosinophilia and the increased production of interleukin 5 (Il-5) in blood and affected tissues. Eosinophils can promote both bronchial smooth muscle contraction and increased permeability of bronchial mucosa. Eosinophil- derived mediators [e.g., granule proteins, reactive oxygen species and leukotriene C4 (LTC4)], can evoke hyper-responsiveness, epithelial damage, inflammation and bronchoconstriction. IL-5 is known to regulate eosinophil function, which can contribute to the pathogenesis of asthma. For example, IL-5 stimulation of blood eosinophils can produce several functional changes that mirror the phenotypic characteristics of the airway eosinophil, and these IL-5-induced changes include the priming LTC4 release, the increased membrane expression of CD11b/CD18, the enhance adherence to endothelial cells, and prolonged survival. Because little is known about IL-5 signal transduction in eosinophils, the present project is designed to explore the mechanisms by which Il-5 mediates alterations in eosinophil function, thereby increasing its inflammatory potential. This proposal will test a model of IL-5 intracellular signaling processes that is based on studies by us and others on the IL-5 family of cytokines. Our overall goal is to assess the importance of various aspects of this model to the intracellular events in human eosinophils stimulated with IL-5, and to relate these signaling processes to eosinophil function. The studies will focus on functional changes, namely chemotaxis, adherence to endothelium, LTC4 generation and suppression of apoptotic cell death, that are of particular relevance to the inflammatory capacity and accumulation of eosinophils in the pathogenesis of asthma. The proposed research centers around our observation that IL-5 stimulates the tyrosine phosphorylation of several cellular proteins, including the phosphorylation and activation of a 45-kDa mitogen- activated protein kinase (MAP kinase). The central hypothesis is developed that multiple pathways are involved in the IL-5 mediated tyrosine phosphorylation and activation of MAP kinases in eosinophils. To test this hypothesis, we will analyze the events that link IL-5 receptor activation to MAP kinase stimulation, such as pathways encompassing tyrosine kinases, Ras, protein kinase C, and/or pertussis toxin-sensitive G-proteins. Secondly, we will also examine selected processes that may result from IL-5-stimulated MAP kinase activity, including the regulation of phospholipase A2, ribosomal S6 kinase II (Rsk) and the hematopoietic transcription factor GATA-2, since these proteins are established MAP kinase substrates. These investigations lead to the related hypothesis that MAP kinase activation is a key intracellular mechanism, that along with other signaling events, is associated with IL-5 mediated changes in eosinophil function, including the priming of LTC4 generation, increased adherence to endothelial cells, chemotaxis and suppression of apoptotic cell death. In sum, it is anticipated that these studies will lead to a greater understanding of the molecular processes associated with eosinophilic inflammation that is a major characteristic of the pathophysiology of asthma.

过敏性炎症和哮喘的特征是嗜酸性粒细胞增多和 白介素5(IL-5)在血液中的生成增加及其影响 纸巾。嗜酸性粒细胞可促进两种支气管壁平滑肌 支气管粘膜收缩，通透性增加。嗜酸性粒细胞- 衍生介体[例如，颗粒蛋白、活性氧物种和 白三烯C4(LTC4)]，可引起高反应性，上皮性 损伤、炎症和支气管收缩。已知IL-5可调节 嗜酸性粒细胞功能，这可能有助于哮喘的发病机制。 例如，IL-5刺激血液中的嗜酸性粒细胞可以产生几种 反映细胞表型特征的功能变化 气道嗜酸性粒细胞，这些IL-5诱导的变化包括启动 LTC4释放，CD11b/CD18膜表达增加， 增强对内皮细胞的黏附，延长存活时间。因为 对嗜酸性粒细胞中IL-5的信号转导知之甚少 本项目旨在探索IL-5 调节嗜酸性粒细胞功能的改变，从而增加其 潜在的炎症。这项提案将测试IL-5的一个模型 细胞内信号传递过程是基于我们和 其他人则属于IL-5细胞因子家族。我们的总体目标是评估 这一模型的各个方面对细胞内的重要性 IL-5刺激的人嗜酸性粒细胞中的事件及其关系 嗜酸性粒细胞功能的信号传递过程。这些研究将集中在 功能变化，即趋化性、内皮细胞黏附、LTC4 产生和抑制凋亡细胞死亡，这是 与炎症能力和蓄积的炎症特别相关 嗜酸性粒细胞在哮喘发病机制中的作用。 拟议的研究围绕着我们观察到的IL-5 刺激几种细胞蛋白的酪氨酸磷酸化， 包括45 kDa有丝分裂原的磷酸化和激活- 活化的蛋白激酶(MAP)。中心假设是 IL-5介导的多种途径参与 嗜酸性粒细胞中酪氨酸磷酸化和MAP激酶的激活。 为了验证这一假设，我们将分析与IL-5相关的事件 受体激活以映射激酶刺激，如通路 包括酪氨酸激酶、RAS、蛋白激酶C和/或百日咳 毒素敏感的G蛋白。其次，我们还将审查精选的 可能是由IL-5刺激的MAP激酶活性引起的过程， 包括对磷脂酶A2、核糖体S6激酶II的调节 (RSK)和造血转录因子GATA-2，因为这些 蛋白质是已建立的MAP激酶底物。这些调查 导致了相关的假设，即MAP激活是一个关键 与其他信号事件一起，细胞内机制是 与IL-5介导的嗜酸性粒细胞功能变化有关，包括 启动LTC4的生成，增加对内皮的黏附 细胞、趋化性和抑制细胞凋亡。总而言之，它 预计这些研究将有助于更好地理解 与嗜酸性炎症相关的分子过程 这是哮喘病理生理学的一个主要特征。