IL-12 p80 Mediated Airway Inflammation

描述(申请人提供)：哮喘的特征是一种不适当的免疫反应，表现为免疫细胞在呼吸道内聚集增加。一般来说，免疫反应分为先天免疫反应和获得性免疫反应，最近的证据表明，先天免疫反应产生炎症介质，为获得性免疫系统提供关键的免疫调节信号。在吸入性物质的炎症反应的特殊背景下，我们提出了呼吸道上皮细胞是天然免疫的主要哨点的理想候选细胞。这种可能性源于观察到这些细胞表达一系列免疫反应基因，为免疫细胞进入、激活和滞留在呼吸道提供关键的免疫调节和生化信号。目前的建议是基于与白介素12家族成员IL-12p80(P80)相关的几个新发现。我们发现，在细胞因子注射、仙台病毒感染和哮喘患者中，呼吸道上皮细胞是产生p80的一种新的细胞来源。此外，仙台病毒感染缺乏IL-12家族另一成员(IL-12 p35)的小鼠过度产生p80，并表现出不适当的炎症，其特征是巨噬细胞在呼吸道中聚集增强。有趣的是，在哮喘患者中，而不是正常或慢性支气管炎患者中，我们再次发现p80过度产生与巨噬细胞聚集增强有关。进一步的研究表明，p80作为巨噬细胞趋化因子发挥作用，而IL-12受体β1链(IL-12Rbeta1)是产生这种依赖于p80的趋化反应的必要条件和充分条件。综上所述，我们的结果将p80过度生产与过度的病毒和哮喘炎症、体内p80生产的新功能后果以及p80依赖的免疫调节特性(如通过IL-12Rbeta1信号介导的巨噬细胞趋化)联系在一起。因此，这项建议的目的是定义依赖p80的巨噬细胞在SDV感染后的聚集，并表征介导这一反应的蛋白质。此外，我们还将定义介导p80依赖的趋化作用的IL-12Rbeta1的结构成分。这些研究将为不适当的病毒性和哮喘呼吸道炎症的发病机制提供洞察力，利用这些知识将提供框架，以开发选择性的p80功能调节器，以调节这种炎症。

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.