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增强气道中免疫细胞的积累。 通常，免疫反应已分为先天和适应性成分，最近的证据表明，先天免疫反应会产生炎症介质，从而为适应性免疫系统提供关键的免疫调节信号。 在对吸入材料的炎症反应的特殊情况下，我们提出了气道上皮细胞代表了成为先天免疫中主要前哨部位的理想候选者。 这种可能性来自观察到这些细胞表达免疫反应基因网络，该基因提供了关键的免疫调节和生化信号，以用于免疫细胞流入，激活和在气道中的保留。 当前的建议基于与白介素（IL）-12家族成员有关的几个新发现，称为IL-12 p80（p80）。 我们将气道上皮细胞鉴定为细胞因子给药，仙台病毒感染以及患有哮喘的受试者的新细胞来源。 此外，缺乏另一个IL-12家族成员（IL-12 p35）的小鼠的仙台病毒感染过量生产P80，并且表现出不适当的炎症，其特征是巨噬细胞在气道中的积累增强。 有趣的是，在哮喘患者（但不是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的积累相关。 进一步的研究表明，p80充当巨噬细胞趋化剂，而IL-12受体β1链（IL-12RBETA1）是必要的，足以产生这种依赖P80依赖性的趋化响应。 综上所述，我们的结果将p80过量生产与过度病毒和哮喘发炎，体内p80产生的新功能后果以及p80依赖性的免疫调节特性（例如巨噬细胞趋化性），例如巨噬细胞趋化性，这些特性是通过IL-12RBETA1信号传递介导的。 因此，该提案的目的是在SDV感染后定义依赖p80依赖性的巨噬细胞积累，并表征介导该反应的蛋白质。 此外，我们将定义介导p80依赖性趋化性的IL-12RBETA1的结构成分。这些研究将提供对不适当病毒和哮喘气道炎症的发病机理的洞察力，对这些知识的开发将为开发p80功能的选择性调节剂提供框架，以调节这种炎症。