Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA
Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA
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DOI：
10.1038/nbt1081
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发表时间：
2005-04-01
影响因子：
46.9
通讯作者：
MacLachlan, I
中科院分区：
文献类型：
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作者：
Judge, AD;Sood, V;MacLachlan, I
通过RNA干扰（RNAi）介导特异性基因沉默的短干扰RNA（siRNA）被广泛用于研究基因功能，并且还被开发用于治疗应用（1）。许多核酸，包括双链RNA（dsRNA）（2）和单链RNA（ssRNA）（3-5），可以刺激哺乳动物的先天细胞因子反应。尽管如此，很少有研究质疑siRNA是否对免疫系统有类似的作用（6，7）。由于与免疫刺激相关的脱靶效应和毒性，这可能会显着影响siRNA的体内应用。在这里，我们报告说，在非病毒载体中配制的合成siRNA可以在小鼠体内和体外人血液中成为干扰素和炎性细胞因子的有效诱导剂。配制的siRNA的免疫刺激活性和相关毒性取决于核苷酸序列。我们已经确定了假定的免疫刺激基序，允许设计可以介导RNAi但诱导最小免疫激活的siRNA。
Short interfering RNAs (siRNAs) that mediate specific gene silencing through RNA interference (RNAi) are widely used to study gene function and are also being developed for therapeutic applications(1). Many nucleic acids, including double- (dsRNA)(2) and single-stranded RNA (ssRNA)(3-5), can stimulate innate cytokine responses in mammals. Despite this, few studies have questioned whether siRNA may have a similar effect on the immune system(6,7). This could significantly influence the in vivo application of siRNA owing to off-target effects and toxicities associated with immune stimulation. Here we report that synthetic siRNAs formulated in nonviral delivery vehicles can be potent inducers of interferons and inflammatory cytokines both in vivo in mice and in vitro in human blood. The immunostimulatory activity of formulated siRNAs and the associated toxicities are dependent on the nucleotide sequence. We have identified putative immunostimulatory motifs that have allowed the design of siRNAs that can mediate RNAi but induce minimal immune activation.