U1 RNA induces innate immunity signaling
U1 RNA induces innate immunity signaling
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DOI：
10.1002/art.20428
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发表时间：
2004-09-01
影响因子：
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通讯作者：
Greidinger, EL
中科院分区：
文献类型：
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作者：
Hoffman, RW;Gazitt, T;Greidinger, EL
Objective. U1-70-kd RNP是结缔组织疾病中自身免疫的突出靶标。在这项研究中，我们探讨了其内源性配体，U1 RNA，介导的促免疫信号，可能是免疫原性。我们检测了对照组和MyD 88敲除组脾细胞对体外合成的U1 RNA的增殖反应，并检测了U1 RNA诱导的人Toll样受体3（TLR-3）和TLR-5信号转导细胞系中白细胞介素-6（IL-6）和IL-8的分泌。用U1 RNA或聚（I-C）（TLR-3的一种已知激动剂）处理诱导的对照脾细胞增殖约为用RNA酶消化的U1 RNA处理的两倍。MyD 88敲除脾细胞对poly（I-C）或U1 RNA的增殖反应也类似地减弱。与poly（I-Q）类似，U1 RNA诱导表达TLR-3的人细胞系显著分泌IL-6和IL-8;相反，TLR-5激动剂鞭毛蛋白主要诱导IL-8分泌。用RNase预处理U1 RNA可抑制IL-6和IL-8的分泌。U1 RNA能够诱导与TLR-3激活一致的表现。U1 RNA（具有大量双链二级结构）激活TLR-3的能力可能有助于U1-70-kd自身抗原的免疫原性。具有双链二级结构的天然RNA分子对先天免疫的刺激可能有助于解释对RNA结合蛋白的自身免疫的高流行率。
Objective. The U1-70-kd RNP is a prominent target of autoimmunity in connective tissue diseases. In this study, we explored whether its endogenous ligand, U1 RNA, mediates a proimmune signal and may be immunogenic.Methods. We assayed the proliferation of control and MyD88-knockout splenocytes in response to in vitro-synthesized U1 RNA, and measured interleukin-6 (IL-6) and IL-8 secretion induced by U1 RNA in a human cell line competent for signaling through Toll-like receptor 3 (TLR-3) and TLR-5.Results. Treatment with U1 RNA or with poly(I-C), a known agonist of TLR-3, induced approximately twice as much control splenocyte proliferation as did treatment with RNase-digested U1 RNA. Proliferation in response to either poly(I-C) or U1 RNA by MyD88-knockout splenocytes was similarly attenuated. Similar to poly(I-Q, U1 RNA induced significant secretion of both IL-6 and IL-8 from a TLR-3-expressing human cell line; in contrast, the TLR-5 agonist flagellin induced predominantly IL-8 secretion. Pretreatment of U1 RNA with RNase abolished IL-6 and IL-8 secretion.Conclusion. U1 RNA is capable of inducing manifestations consistent with TLR-3 activation. The ability of U1 RNA (which has a substantial double-stranded secondary structure) to activate TLR-3 may contribute to the immunogenicity of the U1-70-kd autoantigen. Stimulation of innate immunity by native RNA molecules with a double-stranded secondary structure may help explain the high prevalence of autoimmunity to RNA binding proteins.