慢性鼻-鼻窦炎伴鼻息肉患者鼻黏膜上皮细胞中 IL8 启动子的低甲基化。
Hypomethylation of the IL8 promoter in nasal epithelial cells of patients with chronic rhinosinusitis with nasal polyps.
机构信息
Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China.
Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China; Department of Allergy, Beijing TongRen Hospital, Capital Medical University, Beijing, China.
出版信息
J Allergy Clin Immunol. 2019 Oct;144(4):993-1003.e12. doi: 10.1016/j.jaci.2019.06.042. Epub 2019 Jul 19.
BACKGROUND
IL-8 is an important chemokine implicated in the pathogenesis of chronic rhinosinusitis (CRS), but little is known about epigenetic regulation of IL8 in the pathogenesis of CRS.
OBJECTIVE
We sought to investigate the relationship between the DNA methylation level in the IL8 proximal promoter and CRS in Han Chinese subjects.
METHODS
Patients with chronic rhinosinusitis with nasal polyps (CRSwNP; n = 187), patients with chronic rhinosinusitis without nasal polyps (CRSsNP; n = 89), and control subjects (n = 57) were enrolled in 2 independent cohorts. Purified human nasal epithelial cells from each participant were assessed for percentage DNA methylation of CpG sites in the IL8 proximal promoter by using bisulfite pyrosequencing and for functional aspects of methylation status by using in vitro assays.
RESULTS
DNA methylation of CpG sites 1, 2, and 3, respectively, in the IL8 proximal promoter was significantly decreased in human nasal epithelial cells of patients with CRSwNP compared with that in patients with CRSsNP (P < .001) and control subjects (P < .001). Percentage of DNA methylation of the CpG3 site was correlated negatively with both tissue eosinophilic cationic protein (P < .01) and myeloperoxidase (P < .05) levels. IL-1β (P < .001) and TNF-α (P < .01) significantly increased IL8 expression accompanied by a reduction in methylation at the CpG3 site (P < .001). Electrophoretic mobility shift assays demonstrated that methylation status of CpG3 changed the binding of octamer-binding transcription factor 1 and nuclear factor κB.
CONCLUSION
Decreased DNA methylation of particularly CpG sites in the IL8 proximal promoter might play a role in the pathogenesis of CRSwNP.
背景
白细胞介素-8（IL-8）是慢性鼻-鼻窦炎（CRS）发病机制中的一种重要趋化因子，但关于其在 CRS 发病机制中的表观遗传调控知之甚少。
目的
我们旨在研究 IL8 近端启动子中的 DNA 甲基化水平与汉族人群 CRS 之间的关系。
方法
我们纳入了 2 个独立队列的 187 例慢性鼻-鼻窦炎伴鼻息肉（CRSwNP）患者、89 例慢性鼻-鼻窦炎不伴鼻息肉（CRSsNP）患者和 57 例对照者。通过亚硫酸氢盐焦磷酸测序法检测每个参与者的人鼻上皮细胞中 IL8 近端启动子中 CpG 位点的 DNA 甲基化百分比，并通过体外试验检测甲基化状态的功能方面。
结果
与 CRSsNP 患者（P<0.001）和对照者（P<0.001）相比，CRSwNP 患者的人鼻上皮细胞中 IL8 近端启动子的 CpG 位点 1、2 和 3 的 DNA 甲基化明显降低。CpG3 位点的 DNA 甲基化百分比与组织嗜酸性阳离子蛋白（P<0.01）和髓过氧化物酶（P<0.05）水平均呈负相关。IL-1β（P<0.001）和 TNF-α（P<0.01）显著增加了 IL8 的表达，同时 CpG3 位点的甲基化减少（P<0.001）。电泳迁移率变动分析显示，CpG3 位点的甲基化状态改变了八聚体结合转录因子 1 和核因子 κB 的结合。
结论
IL8 近端启动子中 CpG 位点特别是 CpG3 位点的 DNA 低甲基化可能在 CRSwNP 的发病机制中发挥作用。
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