Oligodeoxynucleotides differentially modulate activation of TLR7 and TLR8 by imidazoquinolines
Oligodeoxynucleotides differentially modulate activation of TLR7 and TLR8 by imidazoquinolines
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DOI：
10.4049/jimmunol.177.11.8164
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发表时间：
2006-12-01
影响因子：
4.4
通讯作者：
Alkan, Sefik S.
中科院分区：
文献类型：
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作者：
Gorden, Keith K. B.;Qiu, Xiaohong;Alkan, Sefik S.
在11个人类tlr中，TLR7、TLR8和TLR9亚家族在结构和内体定位上具有相似性。由核酸组成的天然激动剂，如ssRNA或带有CpG基序的DNA，通过这些tlr激活先天免疫细胞。咪唑喹啉类化合物3M-001、3M-002和3M-003的免疫应答调节剂（IRMs）分别通过TLR7、TLR8和TLR7/8激活先天免疫系统。在观察TLR7、TLR8和TLR9激动剂对转染HEK细胞nf - κ B活化的影响时，我们发现一些低氧脱氧核苷酸（odn）可以以消极或积极的方式调节咪唑喹啉的作用。在这项研究中，我们证明了poly(T) ODNs可以抑制TLR7并增强TLR8信号事件，包括HEK细胞中NF-kappa B的激活和人原代PBMC细胞因子（ifn - α、TNF和IL-12）的产生。相比之下，TLR3激动剂聚（I:C）不影响咪唑喹啉诱导的反应。TLR7和TLR8响应的调节与CpG基序或ODN主干结构的性质无关。此外，我们表明，作为一种有效的调节剂，odn需要与TLR7或TLR8激动剂中的任何一种同时存在于细胞中。我们还证明了irm和odn之间存在物理相互作用。本研究发现的odn、irm与TLR7和TLR8之间的串扰可能在微生物感染、疫苗接种和肿瘤治疗领域具有实际意义。
Among the 11 human TLRs, a subfamily TLR7, TLR8, and TLR9 display similarities in structure and endosomal localization. Natural agonists consisting of nucleic acids, such as ssRNA or DNA with CpG motifs, activate the innate immune cells through these TLRs. Immune response modifiers (IRMs) of imidazoquinoline class compounds 3M-001, 3M-002, and 3M-003 have been shown to activate the innate immune system via TLR7, TLR8, and TLR7/8, respectively. In looking at the effect of the agonists of the TLR7, TLR8, and TLR9 on the activation of NF-kappa B of transfected HEK cells, we discovered that some ofigodeoxynucleotides (ODNs) could modulate imidazoquinoline effects in a negative or positive manner. In this study we demonstrate that poly(T) ODNs can inhibit TLR7 and enhance TLR8 signaling events involving NF-kappa B activation in HEK cells and cytokine production (IFN-alpha, TNF, and IL-12) by human primary PBMC. In contrast, TLR3 agonist poly(I:C) does not affect imidazoquinoline-induced responses. The modulation of TLR7 and TLR8 responses is independent of CpG motifs or the nature of the ODN backbone structure. Furthermore, we show that to be an effective modulator, the ODNs need to be in the cell at the same time with either of the TLR7 or TLR8 agonist. We have also demonstrated that there is a physical interaction between IRMs and ODNs. The cross-talk between ODNs, IRMs, and TLR7 and TLR8 uncovered by this study may have practical implications in the field of microbial infections, vaccination, and tumor therapy.