Double-stranded RNA upregulates the expression of inflammatory mediators in human aortic valve cells through the TLR3-TRIF-noncanonical NF-κB pathway.
Double-stranded RNA upregulates the expression of inflammatory mediators in human aortic valve cells through the TLR3-TRIF-noncanonical NF-κB pathway.
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双链 RNA 通过 TLR3-TRIF-非经典 NF-κB 途径上调人主动脉瓣细胞中炎症介质的表达。
DOI：
10.1152/ajpcell.00230.2016
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Meng,Xianzhong
中科院分区：
文献类型：
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作者：
Zhan,Qiong;Song,Rui;Li,Fei;Ao,Lihua;Zeng,Qingchun;Xu,Dingli;Fullerton,DavidA;Meng,Xianzhong
钙化性主动脉瓣疾病是一种慢性炎症性疾病，主动脉瓣间质细胞（AVIC）的炎症反应在疾病进展中发挥着关键作用。受损或应激细胞释放的双链 RNA (dsRNA) 具有促炎性，可能有助于在患病主动脉瓣中观察到的慢性炎症机制。本研究的目的是确定 dsRNA 对 AVIC 炎症反应的影响及其潜在机制。使用 dsRNA 的模拟物聚肌苷-聚胞苷酸 [poly(I:C)] 刺激来自正常人主动脉瓣的 AVIC。 Poly(I:C) 增加了 IL-6、IL-8、单核细胞趋化蛋白-1 和 ICAM-1 的产生。 Poly(I:C) 还诱导 ERK1/2 和 NF-κB 的强烈激活。 Toll 样受体 3 (TLR3) 或包含 Toll-IL-1 受体结构域的接头诱导 IFN-β (TRIF) 的敲低可抑制 ERK1/2 和 NF-κB p65 磷酸化，并减少聚 (I:C) 诱导的炎症介质产生。 NF-κB（而不是 ERK1/2）的抑制减少了暴露于聚 (I:C) 的 AVIC 中炎症介质的产生。有趣的是，通过阻止 p50 迁移来抑制 NF-κB 并不能抑制炎症介质的产生。通过抑制 p50 迁移，减少 TLR4 激动剂诱导的 NF-κB p65 核内易位；然而，尽管 AVIC 中存在 p65/p50 异二聚体，但聚 (I:C) 诱导的 p65 易位并非如此。 Poly(I:C) 通过 TLR3-TRIF-NF-κB 通路上调人 AVIC 中多种炎症介质的产生。 dsRNA 激活的 NF-κB 似乎不是典型的 p65/p50 异二聚体。
Calcific aortic valve disease is a chronic inflammatory condition, and the inflammatory responses of aortic valve interstitial cells (AVICs) play a critical role in the disease progression. Double-stranded RNA (dsRNA) released from damaged or stressed cells is proinflammatory and may contribute to the mechanism of chronic inflammation observed in diseased aortic valves. The objective of this study is to determine the effect of dsRNA on AVIC inflammatory responses and the underlying mechanism. AVICs from normal human aortic valves were stimulated with polyinosinic-polycytidylic acid [poly(I:C)], a mimic of dsRNA. Poly(I:C) increased the production of IL-6, IL-8, monocyte chemoattractant protein-1, and ICAM-1. Poly(I:C) also induced robust activation of ERK1/2 and NF-κB. Knockdown of Toll-like receptor 3 (TLR3) or Toll-IL-1 receptor domain-containing adapter-inducing IFN-β (TRIF) suppressed ERK1/2 and NF-κB p65 phosphorylation and reduced inflammatory mediator production induced by poly(I:C). Inhibition of NF-κB, not ERK1/2, reduced inflammatory mediator production in AVICs exposed to poly(I:C). Interestingly, inhibition of NF-κB by prevention of p50 migration failed to suppress inflammatory mediator production. NF-κB p65 intranuclear translocation induced by the TLR4 agonist was reduced by inhibition of p50 migration; however, poly(I:C)-induced p65 translocation was not, although the p65/p50 heterodimer is present in AVICs. Poly(I:C) upregulates the production of multiple inflammatory mediators through the TLR3-TRIF-NF-κB pathway in human AVICs. The NF-κB activated by dsRNA appears not to be the canonical p65/p50 heterodimers.