miR-425 通过上调 N-Ras 调节原发性胆汁性胆管炎中 CD4 T 细胞的炎症细胞因子产生。
miR-425 regulates inflammatory cytokine production in CD4 T cells via N-Ras upregulation in primary biliary cholangitis.
机构信息
Division of Advanced Genome Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Gastroenterology and Hepatology, The Jikei University School of Medicine, Tokyo, Japan.
Division of Advanced Genome Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
出版信息
J Hepatol. 2017 Jun;66(6):1223-1230. doi: 10.1016/j.jhep.2017.02.002. Epub 2017 Feb 10.
BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is an autoimmune liver disease of unknown pathogenesis. Consequently, therapeutic targets for PBC have yet to be identified. CD4 T cells play a pivotal role in immunological dysfunction observed in PBC, and therefore, microRNA (miRNA) and mRNA expression were analysed in CD4 T cells, to investigate PBC pathogenesis and identify novel therapeutic targets.
METHODS
Integral miRNA and mRNA analysis of 14 PBC patients and ten healthy controls was carried out using microarray and quantitative real-time polymerase chain reaction (qRT-PCR), with gene set enrichment analysis. The functional analyses of miRNA were then assessed using reporter and miRNA-overexpression assays.
RESULTS
The integral analysis of miRNA and mRNA identified four significantly downregulated miRNAs (miR-181a, -181b, -374b, and -425) related to the T cell receptor (TCR) signalling pathway in CD4 T cells of PBC. N-Ras, a regulator of the TCR signalling pathway, was found to be targeted by all four identified miRNAs. In addition, in vitro assays confirmed that decreased miR-425 strongly induced inflammatory cytokines (interleukin [IL]-2 and interferon [IFN]-γ) via N-Ras upregulation in the TCR signalling pathway.
CONCLUSION
The decreased expression of four miRNAs that dysregulate TCR signalling in PBC CD4 T cells was identified. miR-425 was demonstrated as an inflammatory regulator of PBC via N-Ras upregulation. Therefore, the restoration of decreased miR-425 or the suppression of N-Ras may be a promising immunotherapeutic strategy against PBC.
LAY SUMMARY
Primary biliary cholangitis (PBC) is an autoimmune liver disease, but the causes are unknown. MicroRNAs are molecules known to regulate biological signals. In this study, four microRNAs were identified as being decreased in PBC patients, leading to activation of T cell receptor signalling pathways, involved in inflammation. One particular target, N-Ras, could be an attractive and novel immunotherapeutic option for PBC.
TRANSCRIPT PROFILING
Microarray data are deposited in GEO (GEO accession: GSE93172).
背景与目的
原发性胆汁性胆管炎（PBC）是一种病因不明的自身免疫性肝病。因此，尚未确定 PBC 的治疗靶点。CD4 T 细胞在 PBC 观察到的免疫功能障碍中发挥关键作用，因此，分析了 CD4 T 细胞中的 microRNA（miRNA）和 mRNA 表达，以研究 PBC 的发病机制并确定新的治疗靶点。
方法
使用微阵列和定量实时聚合酶链反应（qRT-PCR）对 14 名 PBC 患者和 10 名健康对照者的整合 miRNA 和 mRNA 进行分析，并进行基因集富集分析。然后使用报告基因和 miRNA 过表达测定来评估 miRNA 的功能分析。
结果
miRNA 和 mRNA 的整体分析确定了 CD4 T 细胞中与 T 细胞受体（TCR）信号通路相关的四个显着下调的 miRNA（miR-181a、-181b、-374b 和 -425）。N-Ras，TCR 信号通路的调节剂，被发现是所有四个鉴定的 miRNA 的靶标。此外，体外测定证实，通过 TCR 信号通路中 N-Ras 的上调，下调的 miR-425 强烈诱导炎症细胞因子（白细胞介素[IL]-2 和干扰素[IFN]-γ）。
结论
在 PBC CD4 T 细胞中，确定了四个失调 TCR 信号的 miRNA 表达降低。miR-425 通过 N-Ras 上调被证明是 PBC 的炎症调节剂。因此，恢复下调的 miR-425 或抑制 N-Ras 可能是一种有前途的针对 PBC 的免疫治疗策略。
概要
原发性胆汁性胆管炎（PBC）是一种自身免疫性肝病，但病因不明。miRNA 是已知调节生物信号的分子。在这项研究中，鉴定出四种 miRNA 在 PBC 患者中减少，导致参与炎症的 T 细胞受体信号通路的激活。特定靶标 N-Ras 可能是 PBC 的一种有吸引力和新颖的免疫治疗选择。
转录谱分析
微阵列数据已存入 GEO（GEO 注册号：GSE93172）。
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