Methylation status of ORMDL3 regulates cytokine production and p-ERK/MMP9 pathway expression
Methylation status of ORMDL3 regulates cytokine production and p-ERK/MMP9 pathway expression
复制标题
ORMDL3 的甲基化状态调节细胞因子的产生和 p-ERK/MMP9 通路的表达
DOI：
10.1016/j.yexcr.2018.09.008
复制
发表时间：
2018-11-01
影响因子：
3.7
通讯作者：
Zhou, Guo-Ping
中科院分区：
文献类型：
--
作者：
Wu, Xiao-Lu;Li, Ran;Zhou, Guo-Ping
Orosomucoid like-3（ORMDL 3）与哮喘的发生、发展密切相关。然而，ORMDL 3在哮喘发病机制中的确切作用仍不清楚。本研究发现ORMDL 3在儿童哮喘患者PBMC中高表达。与对照组相比，儿童哮喘患者细胞因子的产生和p-ERK/MMP-9通路的表达也增加。此外，ORMDL 3过表达诱导IL-6和IL-8释放，并激活p-ERK/MMP-9通路。经5-Aza-CdR处理后，ORMDL 3表达增加。5-Aza-CdR降低了ORMDL 3启动子区CpG岛的比例，提高了其启动子活性。此外，5-Aza-CdR显著增加NHBE细胞中IL-6和IL-8的水平，而敲低ORMDL 3后没有明显变化。在5-Aza-CdR存在或不存在的情况下，ORMDL 3的敲低也显著降低p-ERK/MMP-9通路的表达。总之，我们的研究为ORMDL 3和哮喘相关细胞因子之间的关联提供了新的证据。此外，DNA甲基化在ORMDL 3介导的IL-6和IL-8水平增加以及p-ERK/MMP-9通路表达中起重要作用。
Orosomucoid like-3 (ORMDL3) has been identified to be associated with the development of asthma according to previous studies. However, the definite role of ORMDL3 in the pathogenesis of asthma remains unclear. In this study, we found ORMDL3 was highly expressed in PBMC specimens from childhood asthma patients. Cytokines production and p-ERK/MMP-9 pathway expression was also increased in childhood asthma patients compared with controls. In addition, ORMDL3 overexpression induced IL-6 and IL-8 release and activated p-ERK/MMP-9 pathway in vitro. Increased ORMDL3 expression was observed after treated with 5-Aza-CdR. 5-Aza-CdR decreased the percentage of the CpG island in the ORMDL3 promoter region and increased its promoter activity. In addition, 5-Aza-CdR significantly increased IL-6 and IL-8 levels in NHBE cells while there was no obvious alteration after knocking down ORMDL3. Knockdown of ORMDL3 also significantly decreased the expression of p-ERK/MMP-9 pathway in the presence or absence of 5-Aza-CdR. In conclusion, our study provided novel evidence for the association between ORMDL3 and asthma-associated cytokines. Moreover, DNA methylation plays an important role in ORMDL3-mediated increased IL-6 and IL-8 levels and p-ERK/MMP-9 pathway expression.