STAT3/STAT5基因甲基化调控Th17/Treg细胞因子在PM2.5加重哮喘中的作用

Ambient PM2.5 can exacerbate asthma. In previous studies of our team, we demonstrated that PM2.5 can stimulate an increase of JAK2 and STAT3 gene and protein expressions in human bronchial epithelial cells, and PM2.5 may change the methylation levels of one downstream signal of STAT5, Foxp3 gene in lung of asthma rats, and can decrease the gene transcription levels of TGF-β1. It was shown that STAT3 and STAT5 modulated the differentiation of Th17 cells and Treg cells by RORγt and Foxp3 genes, respectively, which can promote the secretion of corresponding Th17 and Treg cytokines that are involved in the regulation of asthma exacerbation. At present, the research of effects of PM2.5 on DNA methylation of STAT3 and STAT5 has been rarely reported.The relationship between methylation and downstream signaling molecules is not discussed. In this study, population panel study, rat experiment and cell experiment will be performed. Immunofluorescence, pyrosequencing and siRNA will be used to investigate the mechanism of PM2.5 and its aqueous and organic extracts to aggravate asthma based on scientific hypothesis of the regulatory role of STAT3/STAT5 and its DNA methylation on Th17/Treg cytokines, which will provide scientific evidence for the prevention and treatment of asthma, and references of illuminating the mechanism of asthmatic exacerbation induced by PM2.5 and its different constituents.

空气PM2.5可加重人群哮喘发作。课题组前期系列研究表明PM2.5可引起人支气管上皮细胞JAK2和STAT3基因和蛋白表达增加，PM2.5可引起哮喘大鼠肺脏STAT5下游Foxp3基因甲基化改变，细胞因子TGF-β1基因转录降低。研究表明，STAT3和STAT5通过RORγt和Foxp3分别调节Th17和Treg细胞分化，从而产生相应Th17和Treg细胞因子参与哮喘调控。目前PM2.5对STAT3和STAT5的DNA甲基化研究非常少见，二者甲基化与下游信号分子表达的关系尚不清楚。本研究采用人群定组研究、大鼠实验和细胞实验，运用免疫荧光、焦磷酸测序、siRNA等方法，围绕STAT3/STAT5 及其DNA甲基化调控Th17/Treg细胞因子科学假设，探讨PM2.5及其水溶组分、有机组分提取物加重哮喘的机制，为哮喘防治提供科学的靶向资料，为PM2.5及其不同组分加重哮喘发作机制提供参考。

PM2.5是一种主要大气污染物，其成分复杂，与哮喘等疾病显著相关。本研究通过分析PM2.5及其不同组分对哮喘加重的影响，探讨JAK2-STAT3-RORγt、JAK2-STAT5-Foxp3信号通路和Th17/Treg细胞以及STAT3/ RORγt和STAT5/ Foxp3 DNA甲基化在哮喘加重中的调控作用。结果表明，PM2.5及14种多环芳烃、12种重金属和5种水溶性离子具有季节性差异。混合效应模型分析发现，PM2.5与哮喘患者肺功能V50/25有显著相关性。As每增加1ng/m3，FEV1/FVC降低3.84%。PM2.5中BaA、BaP、BbF与肺功能IC呈显著负相关。BpE、DBA、Pb、Cl-与Treg、Th17、Treg/Th17以及鼻粘液中IL-23和TGF-β显著相关。证实了JAK2-STAT3-RORγt和JAK2-STAT5-Foxp3信号通路和Th17/Treg细胞在PM2.5及其不同组分加重大鼠哮喘发作中的调节作用。PM2.5以及水溶、有机染毒高剂量组均可引起p-STAT3、RORγt的基因和蛋白高表达，外周血Th17细胞高表达，Treg细胞比例降低，BALF中IL-23、IL-10和TGF-β1表达增高。PM2.5及各成分均可引起哮喘大鼠STAT3基因甲基化降低，而5-Aza可有效拮抗。PM2.5及其水溶和有机组分可增加Jurkat T细胞JAK2、STAT3和RORγt的基因和蛋白表达，减少STAT5和Foxp3的表达，降低Treg细胞比例，增加IL-17和IL-23的含量，减少IL-10和TGF-β的释放。AG490处理后，信号分子和细胞因子出现逆转。PM2.5及其水溶、有机组分均可引起细胞Foxp3基因甲基化升高，5-aza处理后，甲基化水平明显降低。本研究为认识PM2.5加重哮喘提供了表观遗传学和免疫学线索，对哮喘的治疗和预防提供依据。

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