Hypomethylation of the IL8 promoter in nasal epithelial cells of patients with chronic rhinosinusitis with nasal polyps
Hypomethylation of the IL8 promoter in nasal epithelial cells of patients with chronic rhinosinusitis with nasal polyps
复制标题
慢性鼻窦炎伴鼻息肉患者鼻上皮细胞中 IL8 启动子的低甲基化。
DOI：
10.1016/j.jaci.2019.06.042
复制
发表时间：
2019-10-01
影响因子：
14.2
通讯作者：
Zhang, Luo
中科院分区：
文献类型：
--
作者：
Li, Jingyun;Jiao, Jian;Zhang, Luo
背景资料：IL-8是一种重要的趋化因子，与慢性鼻窦炎（CRS）的发病密切相关，但IL-8在CRS发病中的表观遗传调控机制尚不清楚。目的：探讨IL-8近端启动子区DNA甲基化水平与中国汉族人群CRS发病的关系。研究对象包括慢性鼻窦炎患者（CRSwNP; n = 187）、无鼻息肉的慢性鼻窦炎患者（CRSsNP; n = 89）和对照受试者（n = 57）。通过使用亚硫酸氢盐焦磷酸测序法评估来自每个参与者的纯化的人鼻上皮细胞中IL 8近端启动子中CpG位点的DNA甲基化百分比，并通过使用体外测定法评估甲基化状态的功能方面。CpG位点1、2和3的DNA甲基化，与CRSsNP患者相比，CRSwNP患者的人鼻上皮细胞中IL 8近端启动子的表达显著降低（P <0.001）和对照组（P <0.001）。CpG 3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）水平呈负相关。IL-1 β（P <0.001）和TNF-α（P <0.01）显著增加IL-8表达，伴随着CpG 3位点甲基化的减少（P <0.001）。电泳迁移率改变分析表明，CpG 3甲基化状态改变了八聚体结合转录因子1与核因子κ B的结合。结论：IL 8近端启动子CpG位点的DNA甲基化降低可能在CRSwNP的发病机制中发挥作用。
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-1 beta (P < .001) and TNF-alpha (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 kappa B.Conclusion: Decreased DNA methylation of particularly CpG sites in the IL8 proximal promoter might play a role in the pathogenesis of CRSwNP.