...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7.
【24h】

Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7.

机译：鸟嘌呤核苷类似物的免疫刺激活性的分子基础：Toll样受体7的激活。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Certain C8-substituted and N7, C8-disubstituted guanine ribonucleosides comprise a class of small molecules with immunostimulatory activity. In a variety of animal models, these agents stimulate both humoral and cellular immune responses. The antiviral actions of these guanosine analogs have been attributed to their ability to induce type I IFNs. However, the molecular mechanisms by which the guanosine analogs potentiate immune responses are not known. Here, we report that several guanosine analogs activate Toll-like receptor 7 (TLR7). 7-Thia-8-oxoguanosine, 7-deazaguanosine, and related guanosine analogs activated mouse immune cells in a manner analogous to known TLR ligands, inducing cytokine production in mouse splenocytes (IL-6 and IL-12, type I and II IFNs), bone marrow-derived macrophages (IL-6 and IL-12), and in human peripheral blood leukocytes (type I IFNs, tumor necrosis factor alpha and IL-12). The guanosine congeners also up-regulated costimulatory molecules and MHC I/II in dendritic cells.Genetic complementation studies in human embryonic kidney 293 cells confirmed that the guanosine analogs activate cells exclusively via TLR7. The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. However, TLR8 activation by R-848 and TLR2 activation by [S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-R-Cys-S-Ser-Lys4-OH, trihydrochloride)] were not inhibited by chloroquine, whereas TLR9 activation by CpG oligodeoxynucleotides was abolished. In summary, we present evidence that guanosine analogs activate immune cells via TLR7 by a pathway that requires endosomal maturation. Thus, the B cell-stimulating and antiviral activities of the guanosine analogs may be explained by their TLR7-activating capacity.
机译：某些C8-取代的和N7，C8-二取代的鸟嘌呤核糖核苷包含一类具有免疫刺激活性的小分子。在多种动物模型中，这些物质刺激体液和细胞免疫反应。这些鸟苷类似物的抗病毒作用归因于它们诱导I型IFN的能力。然而，鸟嘌呤类似物增强免疫应答的分子机制尚不清楚。在这里，我们报告说几种鸟苷类似物激活Toll样受体7（TLR7）。 7-Thia-8-oxoguanosine，7-deazaguanosine和相关的鸟苷类似物以类似于已知TLR配体的方式激活小鼠免疫细胞，诱导小鼠脾细胞（IL-6和IL-12，I型和II型IFN）产生细胞因子。 ，骨髓来源的巨噬细胞（IL-6和IL-12）以及人外周血白细胞（I型IFN，肿瘤坏死因子α和IL-12）。鸟嘌呤同源物还上调了树突状细胞中的共刺激分子和MHC I / II。人类胚胎肾293细胞中的基因互补研究证实，鸟嘌呤类似物仅通过TLR7激活细胞。鸟苷类似物在人细胞中刺激TLR7似乎需要内体成熟，因为用氯喹抑制该过程会显着降低NF-κB的下游活化。但是，R-848激活TLR8，[S- [2,3-双（棕榈酰氧基）-（2-RS）-丙基] -N-棕榈酰-R-Cys-S-Ser-Lys4-OH激活TLR2，氯喹不抑制]，而废除了CpG寡脱氧核苷酸对TLR9的激活作用。总而言之，我们提供了鸟苷类似物通过需要内体成熟的途径通过TLR7激活免疫细胞的证据。因此，鸟苷类似物的B细胞刺激和抗病毒活性可以通过它们的TLR7激活能力来解释。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号