A synthetic double-stranded RNA, poly I:C, induces a rapid apoptosis of human CD34+ cells
A synthetic double-stranded RNA, poly I:C, induces a rapid apoptosis of human CD34+ cells
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DOI：
10.1016/j.exphem.2011.12.002
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发表时间：
2012-04-01
影响因子：
2.6
通讯作者：
Sawada, Kenichi
中科院分区：
文献类型：
--
作者：
Liu, Jiajia;Guo, Yong-Mei;Sawada, Kenichi
已知Toll样受体3（TLR 3）、视黄酸诱导基因I和黑素瘤分化相关抗原5（RIG-I/MDA-5）解旋酶可感测双链RNA（dsRNA）病毒并启动抗病毒应答，例如产生I型干扰素（IFN）。TLR 3或RIG-I/MDA-5对dsRNA的识别是细胞类型依赖性的，最近的研究表明TLR与造血之间存在直接联系。我们假设由TLR 3或RIG-I/MDA-5识别的病毒dsRNA影响人造血干/祖细胞的生长。在这里，我们表明，聚肌苷酸多胞苷酸（聚I：C）介导的非常快速的凋亡发生在1小时内的CD 34（+）细胞在剂量依赖性的方式。聚腺苷酸-聚尿苷酸，另一种只通过TLR 3发出信号的合成dsRNA，没有影响。Poly I：C-LMW/LyoVec是低分子量Poly I：C和转染试剂LyoVec之间的复合物，仅通过RIG-I/MDA-5发出信号，诱导CD 34（+）细胞凋亡。在经poly I：C处理的CD 34（+）细胞中发现Noxa的信使RNA和蛋白水平的强烈和持续上调，Noxa是一种仅促凋亡BH 3蛋白，可由RIG-I/MDA-5途径诱导。虽然poly I：C上调CD 34（+）细胞中的I型IFN，但外源性IFN-α和IFN-β均不诱导CD 34（+）细胞的快速凋亡，并且I型IFN受体的中和或阻断不能拯救CD 34（+）细胞，而泛半胱天冬酶抑制剂Z-VAD拯救细胞免于凋亡。这些结果表明，RIG-I/MDA-5，而不是TRL 3，信号触发poly 1：C诱导的人CD 34（+）细胞的快速凋亡，这将提供一个深入了解dsRNA病毒介导的造血系统疾病的机制。(C)2012 ISEH -血液学和干细胞学会。爱思唯尔公司出版
Toll-like receptor 3 (TLR3), retinoic acid-inducible gene I, and melanoma differentiation-associated antigen 5 (RIG-I/MDA-5) helicases are known to sense double-stranded RNA (dsRNA) virus and initiate antiviral responses, such as production of type-I interferons (IFNs). Recognition of dsRNA by TLR3 or RIG-I/MDA-5 is cell-type dependent and recent studies have shown a direct link between TLRs and hematopoiesis. We hypothesized that viral dsRNA recognized by either TLR3 or RIG-I/MDA-5, affects the growth of human hematopoietic stem/progenitor cells. Here we show that polyinosinic polycytidylic acid (poly I:C) mediated very rapid apoptosis occurs within 1 hour in CD34(+) cells in a dose-dependent manner. Polyadenylic-polyuridylic acid, another synthetic dsRNA that signals only through TLR3, had no effect. Poly I:C-LMW/LyoVec, a complex between low molecular-weight poly I:C and the transfection reagent LyoVec, which signals only through RIG-I/MDA-5, induces apoptosis of CD34(+) cells. A strong and sustained upregulation of messenger RNA and protein levels of Noxa, a proapoptotic BH3-only protein that can be induced by RIG-I/MDA-5 pathway, is found in CD34(+) cells treated by poly I:C. Although poly I:C upregulates type-I IFNs in CD34(+) cells, neither exogenous IFN-alpha nor IFN-beta induces rapid apoptosis in CD34(+) cells and neutralization or blocking of type-I IFN receptor does not rescue CD34(+) cells, whereas Z-VAD, a pan-caspase inhibitor, rescues the cells from apoptosis. These results suggest that RIG-I/MDA-5, but not TRL3, signaling triggers poly 1:C induced rapid apoptosis of human CD34(+) cells, which will provide an insight into the mechanisms of dsRNA virus-mediated hematopoietic disorders. (C) 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.