A novel antagonist of TLR9 blocking all classes of immunostimulatory CpG-ODNs
A novel antagonist of TLR9 blocking all classes of immunostimulatory CpG-ODNs
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一种新型 TLR9 拮抗剂，可阻断所有类别的免疫刺激性 CpG-ODN
DOI：
10.1016/j.vaccine.2010.10.042
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发表时间：
2011-03-03
期刊：
影响因子：
5.5
通讯作者：
Zhou, Hong
中科院分区：
文献类型：
--
作者：
Li, Yan;Cao, Hongwei;Zhou, Hong
toll样受体9 （TLR9）对微生物CpG-DNA的识别可能促进过度炎症反应或炎症紊乱。为了防止TLR9激活后可能出现的临床病理损伤，我们利用生物信息学的模式搜索工具研究了一系列来自传统微生物的CpG-DNA序列，并成功地从铜绿假单胞菌基因组中鉴定出CpG-ODN c41，它包含一个新的基序，‘3 x N-CGCG’。通过ELISA和MTT检测，我们发现CpG-ODN c41在小鼠264.7细胞和人单核细胞中具有非刺激性和非细胞毒性，并且能够抑制所有类型的最佳刺激性cpg - dna引起的免疫刺激活性。激光共聚焦显微镜显示，CpG-ODN c41以剂量依赖的方式竞争性地阻断了最佳刺激性cpg - dna与TLR9的结合，从而阻止TLR9触发炎症反应。此外，CpG-ODN c41介导的保护可以通过刺激CpG-ODN在体内接受致命挑战。本研究提示CpG-ODN c41是一种强TLR9拮抗剂，可作为CpG-ODN介导的过度炎症反应的治疗剂，也可用于治疗自身免疫性疾病。(C) 2010年Elsevier Ltd.出版。
The recognition of microbial CpG-DNA by toll-like receptor 9 (TLR9) might promote excessive inflammatory response or inflammatory disorder. To prevent possible clinical pathological injury following the TLR9 activation, here we have investigated a series of CpG-DNA sequences from conventional microbes using a bioinformatics tool of pattern search, and successfully identified CpG-ODN c41 from Pseudomonas aeruginosa genome, which contains a novel motif, '3 x N-CGCG'. Using ELISA and MTT assays, we found that CpG-ODN c41 was non-stimulatory and non-cytotoxic and was able to inhibit the immunostimulatory activity caused by all classes of optimal stimulatory CpG-DNAs in murine 264.7 cells and human monocytes. Laser confocal microscopy demonstrated that CpG-ODN c41 competitively blocked the optimal stimulatory CpG-DNAs from binding to TLR9 in a dose-dependent fashion, thereby preventing TLR9 from triggering the inflammatory response. Moreover, CpG-ODN c41-mediated protection could take up a lethal challenge by stimulatory CpG-ODN in vivo. This study suggests that CpG-ODN c41 is a strong TLR9 antagonist that could be used as a therapeutic agent for CpG-ODN-mediated over-inflammatory responses, may also be used to treat autoimmune diseases. (C) 2010 Published by Elsevier Ltd.