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.

中文翻译：

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IL（白介素）-6促进深静脉血栓形成，并受miR-338-5p负调节。

目的深静脉血栓形成（DVT）是最常见的静脉血栓栓塞性疾病之一，与肺栓塞和血栓形成后综合征密切相关，两者均具有很高的死亡率。但是，触发DVT形成的因素仍然很大程度上未知。IL（白介素）-6（一种重要的炎症细胞因子）的表达升高与DVT的形成有关。但是，尚不清楚导致DVT中IL-6升高的分子机制。在这里，我们提出在转录后水平上IL-6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：为了探讨DVT中microRNA与IL-6之间的关系，我们进行了microRNA微阵列分析和体内外实验。微阵列和实时定量聚合酶链反应结果表明，DVT患者外周血单个核细胞中IL-6表达增加而miR-338-5p水平显着降低，并且miR-338-5p之间呈显着负相关和IL-6。体外实验表明，过表达的miR-338-5p降低了IL-6的表达，而miR-338-5p的降低则提高了IL-6的表达。此外，我们的体内研究发现，具有抗IL-6抗体或agomiR-338-5p递送的小鼠可导致IL-6表达降低并减轻DVT的形成，而antagomiR-338-5p则起相反的作用。通过荧光原位杂交发现大多数miR-338-5p位于细胞质中。双荧光素酶报告基因分析鉴定了miR-338-5p和IL-6之间的直接结合。