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MicroRNA let-7i通过Janus激酶-1及转录因子3信号途径活化因子调节针对IL-10的树突状细胞成熟,进而诱导小鼠移植心脏存活时间延长

MicroRNA let-7i regulates dendritic cells maturation targeting interleukin-10 via the Janus kinase 1-signal transducer and activator of transcription 3 signal pathway subsequently induces prolonged cardiac allograft survival in rats

来源:Scopus 发布时间:2016-5-23
作者:Sun Y, Jin X, Liu X, Zhang M, Liu W, Li Z, Han N, Tan M, Chi D, Zhu J, Zhang B, Yu B, Wu J.
机构: 中国哈尔滨,哈尔滨医科大学第二附属医院心内科;中国教育部心肌缺血重点实验室
期刊: J HEART LUNG TRANSPL 2016年3月3期35卷

Background In this study, we investig1ated whether microRNA let-7i regulates dendric cell maturation targeting interleukin-10 (IL-10) via the Janus kinase 1-signal transducer and activator of transcription 3 (JAK1-STAT3) signal pathway subsequently prolongs rat cardiac allograft survival. Methods Quantitative real-time reverse transcriptase polymerase chain reaction, enzyme linked immunosorbent assay, and dual-luciferase assay were performed to verify whether IL-10 was the target of let-7i, and regulatory T cells were assessed by flow cytometry and immunohistochemical study. Western blot was performed to detect JAK1, STAT3, and phosphorylated STAT3 expression. Lewis recipients of Dark Agouti hearts were transfused with phosphate-buffered saline, lipopolysaccharide (LPS)-mature dendritic cells (mDCs), or let-7i-inhibitor-mDCs. Allograft survival times were recorded, and histologic studies were performed. Results Expression of IL-10 messenger RNA level and production of IL-10 were increased in let-7i-inhibitor-mDCs compared with LPS-mDCs. Luciferase activity showed that the translational level of the IL-10 luciferase reporter was decreased by let-7i mimic but increased by let-7i-inhibitor. MicroRNA let-7i inhibitor suppressed DC maturation; however, pretreatment of IL-10 small interfering RNA attenuated the suppression. Expression of JAK1, STAT3, and phosphorylated STAT3 in mDCs were suppressed by let-7i mimic, and pre-treatment of IL-10 small interfering RNA, however, were upregulated by let-7i inhibitor. Lewis recipients transfused with let-7i-inhibitor-mDCs significantly prolonged Dark Agouti cardiac allograft survival. The allografts transfused with let-7i-inhibitor-mDCs showed slight cell infiltration and significantly preserved graft structure. Inhibition of let-7i increased CD4+CD25+forkhead box P3+ regulatory T cells and modulated cytokine profiles in vivo and in vitro. Conclusions MicroRNA let-7i regulated DC maturation and function targeting IL-10 through the JAK1-STAT3 pathway. Moreover, transfusion of LPS-induced mDCs transfected with let-7i inhibitor induced prolonged cardiac allograft survival and generated regulatory T cells. © 2016 International Society for Heart and Lung Transplantation.

 

通讯作者:Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
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