IL-27作为女性Th2型重症哮喘潜在分子标志物的意义和机理研究

Asthma, especially severe asthma, has obvious sexual bias. Women have an increased prevalence of severe asthma than men, suggesting a role of sex hormones in asthma pathogenesis. However, the molecular mechanisms that regulate sex difference in asthma prevalence and severity remains unclear. IL-27 has been shown to be involved with innate immunity and suppress Th2 response in asthma. The preliminary data demonstrated that IL-27 was downregulated in female asthmatics with high IgE level compared with male asthmatics with high IgE level. The downregulated IL-27 also was correlated with impaired FEV1/FVC and uncontrolled status. We hypothesized that female hormone in association with a Type-2 (IgE) signature would reduce the production of IL-27, and impair the IL-27 restriction of Th2 response, accelerating the Th2 inflammation and immunity dysfunction. To investigate the potential mechanism of female hormone (estrogen) reducing the IL-27 production in asthma, THP-1 cell line was used to evaluate the signaling pathwaysand estrogen receptor in mediating these effects. The results showed estrogen in combination with IL-4 significantly reduced the IL-27 production of THP-1 cells compared with IL-4 or estrogen alone, accompanied with STAT3 activation. In further, interfering STAT3 signaling or estrogen receptor would recover the IL-27 production impaired by combination of estrogen and IL-4. In These intriguing results encourage us to further investigate the clinical interpretation and underlined mechanism of IL-27 down expression in female asthmatics with high Type-2 signature. This project would shed light in the identification of female asthma phenotype and help to develop new strategy for individualized asthma therapy.

最新研究表明哮喘尤其是重症哮喘存在明显性别偏移，女性患者重症哮喘的发生率是男性的近两倍，其病理生理机制和分子生物标志物尚待阐明。IL-27是近年来发现的Th2型免疫负性调节因子，参与哮喘炎症过程。本项目前期研究发现女性Th2型哮喘患者外周血清IL-27表达较男性Th2型哮喘患者显著降低，且与肺功能下降和病情难以控制明显相关；体外实验结果显示雌激素呈浓度依赖性地抑制哮喘单核细胞IL-27表达，与临床样本研究结果一致。我们初步的机理研究表明雌激素下调IL-4诱导的IL-27表达需通过雌激素受体介导，并依赖STAT3细胞内信号通路。本项目拟深入探讨IL-27作为女性Th2型重症哮喘分子标志物的临床价值和意义，并进一步研究雌激素下调哮喘单核细胞IL-27表达的分子机制和潜在治疗靶点，为临床应用IL-27作为哮喘表型的生物标志物和开发哮喘个体化治疗方案提供实验依据。

本研究拟对女性哮喘IL-27水平作为重症哮喘的表型标志物的应用和机制进行研究。在项目期内按照原计划执行，从临床病例收集、临床样本分析、体外机制研究和动物模型探索等多个方面对项目展开研究，计划书中拟定的研究内容目前已经基本完成。我们的研究结果表明，初治哮喘患者血浆IL-27水平较健康对照明显下降，且外周血IL-27水平可以作为初治哮喘患者外周血生物标志物。育龄期哮喘女性较同龄哮喘男性外周血IL-27水平明显降低，提示育龄期女性哮喘患者外周血IL-27水平严重失调。外周血IL-27联合哮喘Th2炎症表型可以预测初治哮喘患者的肺功能和预后。Th2Hi型哮喘患者，外周血IL-27水平与诱导痰中IL-5mRNA水平呈负相关。雌激素联合IL-4对单核细胞分泌IL-27有抑制作用。IL-27（rs153109）基因多态性与哮喘患者外周血IL-27水平相关。哮喘患者雌激素受体α和雌激素受体β表达水平较对照明显升高。哮喘小鼠模型肺组织雌激素受体表达较对照显著升高，参与气道炎症和气道重塑。但哮喘小鼠模型肺组织结果中，雌激素受体表达水平与IL-27表达水平无显著关联。项目研究成果已在同行评议期刊发表学术论文7篇，对哮喘的临床表型和个体化治疗的应用提供了重要的科学数据，有望在临床上得到广泛的应用，为提高哮喘诊治水平和降低医疗负担做出科技贡献。