2'Fluoro Modification Differentially Modulates the Ability of RNAs to Activate Pattern Recognition Receptors.
2'Fluoro Modification Differentially Modulates the Ability of RNAs to Activate Pattern Recognition Receptors.
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DOI：
10.1089/nat.2015.0575
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发表时间：
2016-06
影响因子：
4
通讯作者：
Youngju Lee;Johannes H. Urban;Li Xu;B. Sullenger;Jaewoo Lee
中科院分区：
文献类型：
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作者：
Youngju Lee;Johannes H. Urban;Li Xu;B. Sullenger;Jaewoo Lee
尽管RNA的使用具有巨大的治疗潜力，但这些基于RNA的疗法可能通过激活模式识别受体（PRR）引发不必要的炎症反应，并导致有害的副作用。相比之下，治疗性RNA的免疫激活对于治疗癌症可能是有利的。因此，治疗性RNA的免疫原性应根据RNA的治疗应用而被有意地控制。在这项研究中，我们证明了含有2 '氟（2' F）嘧啶的RNA差异控制PRR的激活。RNA刺激Toll样受体3和7的活性被2 'F嘧啶的掺入所消除。相比之下，2 'F嘧啶的掺入增强了视黄酸诱导的基因1刺激RNA的活性。此外，我们发现，与用2 '羟基5' ppp RNA转染相比，用含有2 'F嘧啶和5'三磷酸（5 'ppp）的RNA转染增加了人癌细胞中的细胞死亡和干扰素-β表达，而含有2' O-甲基嘧啶和5 'ppp的RNA完全消除了细胞中细胞死亡和细胞因子表达的诱导。我们的研究结果表明，2 'F和2' O-甲基核苷的掺入是一种简单的方法，可以根据治疗应用差异控制治疗性RNA激活或限制免疫和炎症反应的能力。
Although the use of RNAs has enormous therapeutic potential, these RNA-based therapies can trigger unwanted inflammatory responses by the activation of pattern recognition receptors (PRRs) and cause harmful side effects. In contrast, the immune activation by therapeutic RNAs can be advantageous for treating cancers. Thus, the immunogenicity of therapeutic RNAs should be deliberately controlled depending on the therapeutic applications of RNAs. In this study, we demonstrated that RNAs containing 2'fluoro (2'F) pyrimidines differentially controlled the activation of PRRs. The activity of RNAs that stimulate toll-like receptors 3 and 7 was abrogated by the incorporation of 2'F pyrimidine. By contrast, incorporation of 2'F pyrimidines enhanced the activity of retinoic acid-inducible gene 1-stimulating RNAs. Furthermore, we found that transfection with RNAs containing 2'F pyrimidine and 5' triphosphate (5'ppp) increased cell death and interferon-β expression in human cancer cells compared with transfection with 2'hydroxyl 5'ppp RNAs, whereas RNAs containing 2'O-methyl pyrimidine and 5'ppp completely abolished the induction of cell death and cytokine expression in the cells. Our findings suggest that incorporation of 2'F and 2'O-methyl nucleosides is a facile approach to differentially control the ability of therapeutic RNAs to activate or limit immune and inflammatory responses depending on therapeutic applications.