IL-12 p80 Mediated Airway Inflammation

超出所提供的空间。哮喘的特点是不适当的免疫反应，表现为气道中免疫细胞的积累增强。一般来说，免疫反应被分为先天和适应性成分，最近的证据表明，先天免疫反应产生炎症介质，为适应性免疫系统提供关键的免疫调节信号。在吸入物质的炎症反应的特殊背景下，我们提出气道上皮细胞是先天免疫中作为主要前哨点的理想候选细胞。这种可能性来源于观察，这些细胞表达免疫反应基因网络，为免疫细胞在气道内的内流、激活和滞留提供关键的免疫调节和生化信号。目前的建议是基于与白细胞介素(IL)-12家族成员IL-12 p80 （p80）有关的几项新发现。我们发现气道上皮细胞是在细胞因子管理、仙台病毒感染和哮喘受试者中产生p80的新细胞来源。此外，仙台病毒感染缺乏另一种IL-12家族成员（IL-12 p35）的小鼠，过量产生p80，并表现出以气道巨噬细胞积累增强为特征的不适当炎症。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作为巨噬细胞的趋化剂和IL-12受体β 1链（IL-12R[31]）是产生这种依赖于p80的趋化反应的必要和充分条件。综上所述，我们的研究结果将p80的过量产生与过度的病毒性和喘息性炎症、体内p80产生的新功能后果以及p80依赖的免疫调节特性（如通过IL-12RI3I信号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依赖性巨噬细胞积聚，并表征介导这种反应的蛋白质。此外，我们将定义介导p80依赖性趋化的IL- 12R_ll的结构成分。这些研究将为不适当的病毒性和哮喘性气道炎症的发病机制提供见解，并利用这些知识将为开发p80功能的选择性调节因子以调节这种炎症提供框架。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. 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-12R[31), 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-12RI3I 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- 12R_ll 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. PERFORMANCE SITE ========================================Section End===========================================