IL-12 p80 Mediated Airway Inflammation

IL-12 p80 介导的气道炎症

• 批准号: 7008095
• 负责人: MICHAEL J WALTER
• 金额: $ 33.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008095
• 关键词: alveolar macrophages; asthma; cell line; chemotaxis; genetically modified animals; inflammation; interleukin 12; laboratory mouse; macrophage; parainfluenza virus type 1; protein structure function; respiratory epithelium; respiratory infections; respiratory virus; tissue /cell culture

DESCRIPTION (provided by applicant): Asthma is characterized by an inappropriate immune response manifested as enhanced accumulation of immune cells in the airway. In general, the immune response has been divided into innate and adaptive components, and recent evidence indicates the innate immune response generates inflammatory mediators that provide critical immunomodulatory signals to the adaptive immune system. In the particular context of the inflammatory response to inhaled materials, we have proposed the airway epithelial cells represent an ideal candidate to act as a primary sentinel site in innate immunity. This possibility was derived from observations that these cells express a network of immune-response genes that provide critical immunomodulatory and biochemical signals for immune cell influx, activation, and retention in the airway. The current proposal is based on several novel findings related to a member of the interleukin (IL)-12 family, called IL-12 p80 (p80). We identified the airway epithelial cell as a novel cellular source for p80 production following cytokine administration, infection with Sendai virus, and in subjects with asthma. Furthermore, Sendai viral infection of mice that lacked another IL-12 family member (IL-12 p35) overproduced p80 and displayed inappropriate inflammation characterized by enhanced accumulation of macrophages in the airway. Interestingly, in asthma subjects, but not normal or chronic bronchitis patients, we again found p80 overproduction that correlated with enhanced macrophage accumulation. Further studies demonstrated p80 functions as a macrophage chemoattractant and the IL-12 receptor beta 1 chain (IL-12Rbeta1) is necessary and sufficient to generate this p80-dependent chemotactic response. Taken together, our results associate p80 overproduction with excessive viral and asthmatic inflammation, new functional consequences of p80 production in vivo, and p80-dependent immunomodulatory properties, such as macrophage chemotaxis, that are mediated through IL-12Rbeta1 signaling. Accordingly, the aims of this proposal are to define p80-dependent macrophage accumulation following SdV infection and characterize the proteins that mediate this response. In addition, we will define the structural components of IL- 12Rbeta1 that mediate p80-dependent chemotaxis. These studies will provide insight into the pathogenesis of inappropriate viral and asthmatic airway inflammation, and exploitation of this knowledge will provide the framework to develop selective regulators of p80 function in order to modulate this inflammation.

描述（由申请人提供）：哮喘的特征是不适当的免疫反应，表现为气道中免疫细胞积累增加。 一般来说，免疫反应分为先天性和适应性部分，最近的证据表明先天性免疫反应会产生炎症介质，为适应性免疫系统提供关键的免疫调节信号。 在对吸入物质的炎症反应的特定背景下，我们提出气道上皮细胞是作为先天免疫中的主要前哨位点的理想候选者。 这种可能性源于对这些细胞表达免疫反应基因网络的观察，这些基因为免疫细胞流入、激活和保留在气道中提供关键的免疫调节和生化信号。 目前的提议基于与白细胞介素 (IL)-12 家族成员（称为 IL-12 p80 (p80)）相关的多项新发现。 我们确定气道上皮细胞是细胞因子施用、仙台病毒感染以及哮喘受试者后 p80 产生的新细胞来源。 此外，缺乏另一种 IL-12 家族成员 (IL-12 p35) 的小鼠感染仙台病毒后，会过量产生 p80，并表现出不适当的炎症，其特征是气道中巨噬细胞的积累增加。 有趣的是，在哮喘受试者中，但在正常或慢性支气管炎患者中，我们再次发现 p80 过量产生，与巨噬细胞积累增强相关。 进一步的研究表明 p80 作为巨噬细胞趋化剂起作用，并且 IL-12 受体 β 1 链 (IL-12Rbeta1) 对于产生这种 p80 依赖性趋化反应是必要且充分的。 总而言之，我们的结果将 p80 过量产生与过度的病毒和哮喘炎症、p80 体内产生的新功能后果以及 p80 依赖性免疫调节特性（例如通过 IL-12Rbeta1 信号传导介导的巨噬细胞趋化性）联系起来。 因此，本提案的目的是定义 SdV 感染后 p80 依赖性巨噬细胞的积累，并表征介导这种反应的蛋白质。 此外，我们将定义介导 p80 依赖性趋化作用的 IL-12Rbeta1 的结构成分。这些研究将深入了解不适当的病毒和哮喘气道炎症的发病机制，并且利用这些知识将为开发 p80 功能的选择性调节剂以调节这种炎症提供框架。