Chapin William J, Lenkala Divya, Mai Yifeng, Mao Yushan, White Steven R, Huang Rong S
aPritzker School of Medicine bDepartment of Medicine, University of Chicago, Chicago, Illinois, USA cThe Affiliated Hospital of Ningbo University, Ningbo, China.
Pharmacogenet Genomics. 2015 Mar;25(3):126-33. doi: 10.1097/FPC.0000000000000116.
Despite of the common usage of glucocorticoids (GCs), a significant portion of asthma patients exhibit GC insensitivity. This could be mediated by diverse mechanisms, including genomics. Recent work has suggested that measuring changes in gene expression may provide more predictive information about GC insensitivity than baseline gene expression alone, and that expression changes in peripheral blood may be reflective of those in the airway.
We performed in silico discovery using gene expression omnibus (GEO) data that evaluated GC effect on gene expression in multiple tissue types. Subsequently, candidate genes whose expression levels are affected by GC were examined in cell lines and in primary cells derived from human airway and blood.
Through gene expression omnibus analysis, we identified interferon regulator factor 1 (IRF1), whose expression is affected by GC treatment in airway smooth muscle cells, normal human bronchial epithelial (NHBE) cells, and lymphoblastoid cell lines (LCLs). Significant IRF1 downregulation post GC exposure was confirmed in two cultured airway epithelial cell lines and primary NHBE cells (P<0.05). We observed large interindividual variation in GC-induced IRF1 expression changes among primary NHBE cells tested. Significant downregulation of IRF1 was also observed in six randomly selected LCLs (P<0.05), with variable degrees of downregulation among different samples. In peripheral blood mononuclear cells obtained from healthy volunteers, variable downregulation of IRF1 by GC was also shown. NFKB1, a gene whose expression is known to be downregulated by GC and the degree of downregulation of which is reflective of GC response, was used as a control in our study. IRF1 shows more consistent downregulation across tissue types when compared with NFKB1.
Our results suggest that GC-induced IRF1 gene expression changes in peripheral blood could be used as a marker to reflect GC response in the airway.
尽管糖皮质激素（GCs）被广泛使用，但仍有相当一部分哮喘患者表现出对GC不敏感。这可能由多种机制介导，包括基因组学。最近的研究表明，测量基因表达的变化可能比单独的基线基因表达提供更多关于GC不敏感的预测信息，并且外周血中的表达变化可能反映气道中的变化。
我们使用基因表达综合数据库（GEO）数据进行了计算机模拟发现，该数据评估了GC对多种组织类型中基因表达的影响。随后，在细胞系以及源自人气道和血液的原代细胞中检测了表达水平受GC影响的候选基因。
通过基因表达综合分析，我们鉴定出干扰素调节因子1（IRF1），其在气道平滑肌细胞、正常人支气管上皮（NHBE）细胞和成淋巴细胞系（LCLs）中的表达受GC处理影响。在两种培养的气道上皮细胞系和原代NHBE细胞中证实，GC暴露后IRF1显著下调（P<0.05）。我们观察到在测试的原代NHBE细胞中，GC诱导的IRF1表达变化存在较大的个体间差异。在六个随机选择的LCLs中也观察到IRF1的显著下调（P<0.05），不同样本中的下调程度各不相同。在从健康志愿者获得的外周血单核细胞中，也显示出GC对IRF1的不同程度下调。NFKB1是一种已知其表达受GC下调且下调程度反映GC反应的基因，在我们的研究中用作对照。与NFKB1相比，IRF1在不同组织类型中表现出更一致的下调。
我们的结果表明，外周血中GC诱导的IRF1基因表达变化可作为反映气道中GC反应的标志物。
