IL (Interleukin)-6 Contributes to Deep Vein Thrombosis and Is Negatively Regulated by miR-338-5p
IL (Interleukin)-6 Contributes to Deep Vein Thrombosis and Is Negatively Regulated by miR-338-5p
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IL（白细胞介素）-6 导致深静脉血栓形成并受 miR-338-5p 负调控
DOI：
10.1161/atvbaha.119.313137
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发表时间：
2020-02-01
影响因子：
8.7
通讯作者：
Li, Xia
中科院分区：
文献类型：
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作者：
Zhang, Yunhong;Zhang, Zhen;Li, Xia
补充数字内容可在文本中找到。目的：深静脉血栓形成（Deep venous thrombosis， DVT）是最常见的静脉血栓栓塞性疾病之一，与肺栓塞和血栓后综合征密切相关，两者的死亡率都很高。然而，引发深静脉血栓形成的因素在很大程度上仍是未知的。IL（白细胞介素）-6（一种重要的炎症细胞因子）的表达升高与DVT的形成有关。然而，导致DVT中IL-6升高的分子机制尚不清楚。在这里，我们提出IL-6在转录后水平的表观遗传修饰可能是DVT中IL-6上调的关键触发因素。方法和结果：为了探索microRNA与IL-6在DVT中的关系，我们进行了microRNA芯片分析和体内外实验。芯片和实时定量聚合酶链反应结果显示，DVT患者外周血单个核细胞中IL-6表达升高，miR-338-5p水平明显降低，且miR-338-5p与IL-6呈显著负相关。体外实验表明，过表达miR-338-5p可降低IL-6的表达，而敲低miR-338-5p可增加IL-6的表达。此外，我们的体内研究发现，抗IL-6抗体或给药agomiR-338-5p的小鼠IL-6表达降低，DVT形成减轻，而antagomiR-338-5p则相反。荧光原位杂交发现大部分miR-338-5p位于细胞质中。双荧光素酶报告试验确定了miR-338-5p与IL-6之间的直接结合。结论：我们的研究结果表明，miR-338-5p的降低通过增加IL-6的表达来促进DVT的形成。
Supplemental Digital Content is available in the text. Objective: Deep venous thrombosis (DVT), one of the most common venous thromboembolic disorders, is closely linked with pulmonary embolism and post-thrombotic syndrome, both of which have a high mortality. However, the factors that trigger DVT formation are still largely unknown. Elevated expression of IL (interleukin)-6—an important inflammatory cytokine—has been linked with DVT formation. However, the molecular mechanisms leading to the elevated IL-6 in DVT remain unclear. Here, we proposed that epigenetic modification of IL-6 at the post-transcriptional level may be a crucial trigger for IL-6 upregulation in DVT. Approach and Results: To explore the association between microRNAs and IL-6 in DVT, we performed microRNA microarray analysis and experiments both in vitro and in vivo. Microarray and quantitative real-time polymerase chain reaction results showed that IL-6 expression was increased while miR-338-5p level was decreased substantially in peripheral blood mononuclear cells of patients with DVT, and there was significant negative correlation between miR-338-5p and IL-6. Experiments in vitro showed that overexpressed miR-338-5p reduced IL-6 expression, while miR-338-5p knockdown increased IL-6 expression. Moreover, our in vivo study found that mice with anti–IL-6 antibody or agomiR-338-5p delivery resulted in decreased IL-6 expression and alleviated DVT formation, whereas antagomiR-338-5p acted inversely. Most of miR-338-5p was found located in cytoplasm by fluorescence in situ hybridization. Dual-luciferase reporter assay identified direct binding between miR-338-5p and IL-6. Conclusions: Our results suggest that decreased miR-338-5p promotes DVT formation by increasing IL-6 expression.