Double-stranded RNAs from the helminth parasite Schistosoma activate TLR3 in dendritic cells
Double-stranded RNAs from the helminth parasite Schistosoma activate TLR3 in dendritic cells
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DOI：
10.1074/jbc.m411223200
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发表时间：
2005-01-07
影响因子：
4.8
通讯作者：
Trottein, F
中科院分区：
文献类型：
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作者：
Aksoy, E;Zouain, CS;Trottein, F
寄生虫曼氏血吸虫卵期对树突状细胞（DCs）的刺激激活了导致I型干扰素（IFN）和IFN刺激基因（ISG）表达的信号传导途径。在这里，我们证明了S。mansoni卵不连续地激活DC中的髓样分化因子88（MyD 88）依赖性和MyD 88非依赖性途径。MyD 88缺陷小鼠DC中炎性细胞因子表达和NF-κ B活化受损，而MyD 88或Toll样受体（TLR）4缺陷小鼠中信号转导转录激活因子（STAT）1（（Tyr 701））磷酸化和ISG表达完整。因此，我们分析了不同的TLR成员对卵裂体卵的应答能力，并确定TLR 3导致NF-κ B和IFN-β启动子的正调控结构域III-I位点的激活。出乎意料的是，鸡蛋衍生的RNA具有RNase A-抗性和RNase III-敏感的结构，能够触发TLR 3激活，这表明双链（ds）结构的参与。此外，来自TLR 3缺陷小鼠的DC显示出对来自卵的dsRNA的响应的信号转导转录激活因子1磷酸化和ISG表达的完全丧失。最后，TLR 3-缺陷型DC显示相对于野生型细胞减少的对溶酶体卵的反应。总的来说，我们的数据首次表明，来自非病毒病原体的dsRNA可以通过TLR 3作为先天免疫系统的诱导剂。
Stimulation of dendritic cells (DCs) by the egg stage of the helminth parasite Schistosoma mansoni activates a signaling pathway resulting in type I interferon (IFN) and IFN-stimulated gene (ISG) expression. Here, we demonstrate that S. mansoni eggs disjointedly activate myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent pathways in DCs. Inflammatory cytokine expression and NF-kappaB activation in DCs from MyD88-deficient mice were impaired, whereas signaling transducer activator of transcription ( STAT) 1((Tyr701)) phosphorylation and ISG expression were intact in MyD88 or Toll-like receptor (TLR)4-deficient counterparts. Accordingly, we analyzed distinct TLR members for their ability to respond to schistosome eggs and established that TLR3 resulted in the activation of NF-kappaB and the positive regulatory domain III-I site from IFN-beta promoter. Unexpectedly, egg-derived RNA possessed RNase A-resistant and RNase III-sensitive structures capable of triggering TLR3 activation, suggesting the involvement of double-stranded (ds) structures. Moreover, DCs from TLR3-deficient mice displayed a complete loss of signaling transducer activator of transcription 1 phosphorylation and ISG expression in response to egg-derived dsRNA. Finally, TLR3-deficient DCs showed a reduced response to schistosome eggs relative to wild-type cells. Collectively, our data suggest for the first time that dsRNA from a non-viral pathogen may act as an inducer of the innate immune system through TLR3.