Laboratory of Bioinformatics and Genomics, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
BMC Med Genomics. 2012 Jun 19;5:27. doi: 10.1186/1755-8794-5-27.
Asthma is a chronic inflammatory airway disease influenced by genetic and environmental factors that affects ~300 million people worldwide, leading to ~250,000 deaths annually. Glucocorticoids (GCs) are well-known therapeutics that are used extensively to suppress airway inflammation in asthmatics. The airway epithelium plays an important role in the initiation and modulation of the inflammatory response. While the role of GCs in disease management is well understood, few studies have examined the holistic effects on the airway epithelium.
Gene expression data were used to generate a co-transcriptional network, which was interrogated to identify modules of functionally related genes. In parallel, expression data were mapped to the human protein-protein interaction (PPI) network in order to identify modules with differentially expressed genes. A common pathways approach was applied to highlight genes and pathways functionally relevant and significantly altered following GC treatment.
Co-transcriptional network analysis identified pathways involved in inflammatory processes in the epithelium of asthmatics, including the Toll-like receptor (TLR) and PPAR signaling pathways. Analysis of the PPI network identified RXRA, PPARGC1A, STAT1 and IRF9, among others genes, as differentially expressed. Common pathways analysis highlighted TLR and PPAR signaling pathways, providing a link between general inflammatory processes and the actions of GCs. Promoter analysis identified genes regulated by the glucocorticoid receptor (GCR) and PPAR pathways as well as highlighted the interferon pathway as a target of GCs.
Network analyses identified known genes and pathways associated with inflammatory processes in the airway epithelium of asthmatics. This workflow illustrated a hypothesis generating experimental design that integrated multiple analysis methods to produce a weight-of-evidence based approach upon which future focused studies can be designed. In this case, results suggested a mechanism whereby GCs repress TLR-mediated interferon production via upregulation of the PPAR signaling pathway. These results highlight the role of interferons in asthma and their potential as targets of future therapeutic efforts.
哮喘是一种由遗传和环境因素影响的慢性炎症性气道疾病，全球约有 3 亿人受其影响，每年导致约 25 万人死亡。糖皮质激素（GCs）是一种众所周知的治疗药物，广泛用于抑制哮喘患者的气道炎症。气道上皮在炎症反应的启动和调节中起着重要作用。虽然 GCs 在疾病管理中的作用已被充分了解，但很少有研究检查其对气道上皮的整体影响。
使用基因表达数据生成共转录网络，通过该网络识别功能相关基因的模块。同时，将表达数据映射到人类蛋白质-蛋白质相互作用（PPI）网络，以识别具有差异表达基因的模块。应用共同途径方法突出显示 GC 治疗后功能相关和显著改变的基因和途径。
共转录网络分析确定了哮喘患者气道上皮中涉及炎症过程的途径，包括 Toll 样受体（TLR）和 PPAR 信号通路。对 PPI 网络的分析确定了 RXRA、PPARGC1A、STAT1 和 IRF9 等基因作为差异表达基因。共同途径分析突出了 TLR 和 PPAR 信号通路，为一般炎症过程和 GCs 作用之间提供了联系。启动子分析确定了受糖皮质激素受体（GCR）和 PPAR 途径调节的基因，并强调了干扰素途径是 GCs 的靶点。
网络分析确定了与哮喘患者气道上皮炎症过程相关的已知基因和途径。该工作流程说明了一种生成假设的实验设计，该设计集成了多种分析方法，为未来的重点研究提供了基于证据的方法。在这种情况下，结果表明 GCs 通过上调 PPAR 信号通路来抑制 TLR 介导的干扰素产生的机制。这些结果强调了干扰素在哮喘中的作用及其作为未来治疗努力靶点的潜力。
