Huang Fung-Yu, Chan Annie On-On, Rashid Asif, Wong Danny Ka-Ho, Seto Wai-Kay, Cho Chi-Hin, Lai Ching-Lung, Yuen Man-Fung
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China.
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China; Gastroenterology and Hepatology Center, The Hong Kong Sanatorium and Hospital, Hong Kong, SAR, P.R. China.
Oncol Lett. 2016 Apr;11(4):2919-2924. doi: 10.3892/ol.2016.4296. Epub 2016 Mar 1.
Interleukin-1β (IL-1β) has a significant role in chronic gastric inflammation and manifestations of gastric diseases. The present study aimed to elucidate the specific role of IL-1β in induction of DNA methylation using IL-1 receptor type 1 knockout (IL-1R1/) mice. In the present study, wild-type (WT) and IL-1R1/ mice were injected with IL-1β (5 µg/kg/day). Serum levels of IL-1β, interleukin-6 (IL-6) and nitric oxide (NO) were measured by enzyme-linked immunosorbent or NO assays. E-cadherin (E-cad) methylation status and messenger (m)RNA expression of IL-1β, IL-6, E-cad and inducible nitric oxide synthase (iNOS) were analyzed. Results from the present study indicated significantly higher IL-1β mRNA expression (P<0.001) in WT mice compared with IL-1R1/ mice. IL-1β and IL-6 release was significantly increased in treated WT mice compared with IL-1R1/ mice at 1 h, 4 h and 8 h (all P<0.005). IL-1β release was only detected in WT mice following a second dose measured at day 3, week 1 and week 2 when compared with IL-1R1/ mice. Promoter methylation of E-cad and a decrease in gene expression was observed in treated WT mice. mRNA expression of iNOS in WT mice was significantly increased at week 1 compared with IL-1R1/ mice (P=0.0411). Furthermore, a significantly increased level of NO production was observed in treated WT mice (P<0.005 at 8 h and week 1; P<0.001 at 4 h and day 3) when compared with IL-1R1/ mice. The present results indicated that IL-1β was able to directly induce DNA methylation, which may link inflammation-induced epigenetic changes and the development of gastric diseases.
白细胞介素-1β（IL-1β）在慢性胃炎症和胃部疾病表现中起重要作用。本研究旨在利用1型白细胞介素-1受体敲除（IL-1R1⁻/⁻）小鼠阐明IL-1β在诱导DNA甲基化中的具体作用。在本研究中，野生型（WT）和IL-1R1⁻/⁻小鼠注射IL-1β（5μg/kg/天）。通过酶联免疫吸附或NO测定法测量血清中IL-1β、白细胞介素-6（IL-6）和一氧化氮（NO）水平。分析IL-1β、IL-6、E-钙黏蛋白（E-cad）和诱导型一氧化氮合酶（iNOS）的E-cad甲基化状态和信使（m）RNA表达。本研究结果表明，与IL-1R1⁻/⁻小鼠相比，WT小鼠中IL-1β mRNA表达显著更高（P<0.001）。与IL-1R1⁻/⁻小鼠相比，在1小时、4小时和8小时时，经处理的WT小鼠中IL-1β和IL-6释放显著增加（所有P<0.005）。与IL-1R1⁻/⁻小鼠相比，在第3天、第1周和第2周测量的第二剂后仅在WT小鼠中检测到IL-1β释放。在经处理的WT小鼠中观察到E-cad启动子甲基化和基因表达降低。与IL-1R1⁻/⁻小鼠相比，WT小鼠中iNOS的mRNA表达在第1周时显著增加（P=0.0411）。此外，与IL-1R1⁻/⁻小鼠相比，在经处理的WT小鼠中观察到NO产生水平显著增加（8小时和第1周时P<0.005；4小时和第3天时P<0.001）。本研究结果表明，IL-1β能够直接诱导DNA甲基化，这可能将炎症诱导的表观遗传变化与胃部疾病的发展联系起来。
