在丙型肝炎病毒（HCV）患者的自然杀伤（NK）细胞中，微小RNA-29a*抑制PU.1，会减弱其对HCV感染细胞模型的细胞溶解作用。
Repressing PU.1 by miR-29a∗ in NK cells of HCV patients, diminishes its cytolytic effect on HCV infected cell models.
作者信息
Elemam Noha Mousaad, Mekky Radwa Yehia, El-Ekiaby Nada Magdy, El Sobky Shereen Ahmed, El Din Mohammad Ahmad Mohey, Esmat Gamal, Abdelaziz Ahmed Ihab
机构信息
The Molecular Pathology Research Group, Department of Pharmacology and Toxicology, German University in Cairo, New Cairo City, Main Entrance Al Tagamoa Al Khames, 11835 Cairo, Egypt.
The Molecular Pathology Research Group, Department of Pharmaceutical Biology, German University in Cairo, New Cairo City, Main Entrance Al Tagamoa Al Khames, 11835 Cairo, Egypt.
出版信息
Hum Immunol. 2015 Sep;76(9):687-94. doi: 10.1016/j.humimm.2015.09.021. Epub 2015 Sep 30.
OBJECTIVES
Natural killer cells are immune safeguards against HCV infection. PU.1 is a pivotal transcription factor in the development of NK cells. This study aimed at studying the regulatory effect of miRNAs on both development and function of NK cells isolated from HCV patients.
METHODS
NK cells were isolated from 17 chronic HCV patients and 12 healthy controls; after which miRNA and mRNA were quantified using qRT-PCR. Manipulating miRNA expression using mimics and antagomirs, was performed followed by investigating downstream targets as well as viral abundance.
RESULTS
PU.1 expression levels were upregulated in NK cells of HCV patients. In silico analysis revealed PU.1 to be a potential downstream target of miR-29a(∗), where miR-29a(∗) overexpression in NK cells caused a significant downregulation in PU.1 mRNA. Forcing miR-29a(∗) caused a downregulation of the cytotoxicity determinant NK activating receptor (NKG2D) via upregulation of miR-155. Moreover, perforin-1 mRNA was found to be downregulated upon forcing the expression of miR-29a(∗) in NK cells of HCV patients. This decrease in NK cytolytic function was accompanied by an 80% viral load increase in cocultured HCVcc cell models.
CONCLUSIONS
This study showed that HCV infection might abrogate NK cytotoxic potential through altering PU.1, NKG2D receptor and perforin molecules.
目的
自然杀伤细胞是抵御丙型肝炎病毒（HCV）感染的免疫卫士。PU.1是自然杀伤细胞发育过程中的关键转录因子。本研究旨在探讨微小RNA（miRNA）对从HCV患者中分离出的自然杀伤细胞的发育和功能的调节作用。
方法
从17例慢性HCV患者和12名健康对照者中分离出自然杀伤细胞；随后使用定量逆转录聚合酶链反应（qRT-PCR）对miRNA和信使核糖核酸（mRNA）进行定量分析。使用模拟物和拮抗剂操纵miRNA表达，然后研究下游靶点以及病毒丰度。
结果
HCV患者自然杀伤细胞中PU.1的表达水平上调。生物信息学分析显示PU.1是miR-29a（）的潜在下游靶点，其中在自然杀伤细胞中过表达miR-29a（）会导致PU.1 mRNA显著下调。强制表达miR-29a（）会通过上调miR-155导致细胞毒性决定因素自然杀伤细胞激活受体（NKG2D）下调。此外，在HCV患者的自然杀伤细胞中强制表达miR-29a（）后，穿孔素-1 mRNA被发现下调。自然杀伤细胞溶细胞功能的这种下降伴随着共培养的HCVcc细胞模型中病毒载量增加80%。
结论
本研究表明，HCV感染可能通过改变PU.1、NKG2D受体和穿孔素分子来消除自然杀伤细胞的细胞毒性潜力。
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