2'-O-methyl-modified RNAs act as TLR7 antagonists
2'-O-methyl-modified RNAs act as TLR7 antagonists
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DOI：
10.1038/sj.mt.6300240
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发表时间：
2007-09-01
影响因子：
12.4
通讯作者：
MacLachlan, Ian
中科院分区：
文献类型：
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作者：
Robbins, Marjorie;Judge, Adam;MacLachlan, Ian
单链RNA(SsRNA)和小干扰RNA(SiRNA)等RNA分子在细胞内递送后可诱导Toll样受体(TLR)介导的免疫刺激。我们以前已经证明，选择性地将2‘-O-甲基(2’OME)残基掺入siRNA可以在不降低基因沉默活性的情况下取消细胞因子的产生。在这里，我们展示了2‘OME修饰的RNA在人类和小鼠系统中作为RNA介导的细胞因子诱导的有效抑制物。这种活性不需要将2‘OME核苷酸直接掺入免疫刺激RNA中，也不需要将含有2’OME核苷酸的RNA作为互补链进行退火以形成双链。我们的结果表明，2‘OME RNA是一种有效的免疫刺激RNA拮抗剂。我们进一步证明，2‘OME RNA能够显著降低小分子TLR7激动剂洛索里宾对人外周血单个核细胞(PBMC)、小鼠Flt3L树突状细胞(Flt3L DC)和小鼠体内诱导的干扰素-α(IFN-α)和白细胞介素6(IL-6)的诱导。这些结果表明，2‘OME修饰的RNA可能作为TLR7的抑制剂，在涉及TLR7介导的免疫刺激的炎症性疾病和自身免疫性疾病的治疗中具有潜在的应用价值。
RNA molecules such as single-stranded RNA ( ssRNA) and small interfering RNA ( siRNA) duplexes induce Toll-like receptor (TLR)-mediatedimmune stimulation after intracellular delivery. We have previously shown that selective incorporation of 2'-O-methyl(2'OMe) residues into siRNA abrogates cytokine production without reduction of gene silencing activity. Here we show that 2' OMe-modified RNA acts as a potent inhibitor of RNA- mediated cytokine induction in both human and murine systems. This activity does not require the direct incorporation of 2'OMe nucleotides into the immunostimulatory RNA or that the 2' OMe nucleotide-containing RNA be annealed as a complementary strand to form a duplex. Our results indicate that 2'OMe RNA acts as a potent antagonist of immunostimulatory RNA. We further show that 2' OMe RNA is able significantly to reduce both interferon-alpha (IFN alpha) and interleukin-6 ( IL- 6) induction by the small-molecule TLR7 agonist loxoribine in human peripheral blood mononuclear cells ( human PBMCs), in murine Flt3L dendritic cells ( Flt3L DCs), and in vivo in mice. These results indicate that 2' OMe- modified RNA may have utility as an inhibitor of TLR7 with potential applications in the treatment of inflammatory and autoimmune diseases that involve TLR7- mediated immune stimulation.