A synthetic double-stranded RNA, poly I:C, induces a rapid apoptosis of human CD34⁺ cells

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• 作者：Jiajia Liu^a ; ^&lowast ; ; Yong-Mei Guo^a ; ^&lowast ; ; Makoto Hirokawa^b ; Keiko Iwamoto^a ; Kumi Ubukawa^a ; Yoshihiro Michishita^a ; Naohito Fujishima^c ; Hiroyuki Tagawa^a ; Naoto Takahashi^a ; Weiguo Xiao^d ; Junsuke Yamashita^e ; Toshiaki Ohteki^f ; ^g ; Kenichi Sawada^a ; ^{ksawada@doc.med.akita-u.ac.jp}
• 刊名：Experimental Hematology
• 出版年：2012
• 期刊代码：100_0301472x
• 类别：med
• 出版时间：April, 2012
• 卷：40
• 期：4
• 页码：330-341
• 文件大小：1685 K

摘要

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聽in CD34⁺ cells treated by poly I:C. Although poly I:C upregulates type-I IFNs in CD34⁺ cells, neither exogenous IFN-伪 nor IFN-尾 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 I:C-induced rapid apoptosis of human CD34⁺聽cells, which will provide an insight into the mechanisms of dsRNA virus-mediated hematopoietic disorders.