Clarithromycin prevents human respiratory syncytial virus-induced airway epithelial responses by modulating activation of interferon regulatory factor-3
Clarithromycin prevents human respiratory syncytial virus-induced airway epithelial responses by modulating activation of interferon regulatory factor-3
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DOI：
10.1016/j.phrs.2016.07.033
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发表时间：
2016-09-01
影响因子：
9.3
通讯作者：
Yokota, Shin-ichi
中科院分区：
文献类型：
--
作者：
Yamamoto, Keisuke;Yamamoto, Soh;Yokota, Shin-ichi
大环内酯类抗生素通过减少呼吸道上皮细胞、成纤维细胞、血管内皮细胞和免疫细胞产生促炎细胞因子而发挥免疫调节活性。然而，潜在的行动机制仍不清楚。在这里，我们检测了克拉霉素(CAM)对原代人鼻上皮细胞和肺上皮细胞系(A549和BEAS-2B细胞)在Toll样受体(TLR)和Rig-I样受体(RLR)激动剂刺激下以及在人呼吸道合胞病毒(RSV)感染后对包括干扰素(IFN)在内的促炎细胞因子产生的影响。CaM处理后，Poly I：C和RSV介导的IL-8、CCL5、干扰素-β和-lambda的产生显著减少。此外，经CAM处理后，干扰素-β启动子活性(由PolyI：C和RSV感染激活)显著降低。CaM还抑制IRF-3的二聚化和随后的核转位。我们得出结论，CAM通过调节IRF-3的二聚化和随后的转位到呼吸道上皮细胞的细胞核，对先天性免疫反应，特别是干扰素的产生起着至关重要的调节作用。这种新发现的CAM的免疫调节作用将有助于发现具有抗炎作用的新的大环内酯类化合物。(C)2016爱思唯尔有限公司。保留所有权利。
Macrolide antibiotics exert immunomodulatory activity by reducing pro-inflammatory cytokine production by airway epithelial cells, fibroblasts, vascular endothelial cells, and immune cells. However, the underlying mechanism of action remains unclear. Here, we examined the effect of clarithromycin (CAM) on pro-inflammatory cytokine production, including interferons (IFNs), by primary human nasal epithelial cells and lung epithelial cell lines (A549 and BEAS-2B cells) after stimulation by Toll-like receptor (TLR) and RIG-I-like receptor (RLR) agonists and after infection by human respiratory syncytial virus (RSV). CAM treatment led to a significant reduction in poly I:C-and RSV-mediated IL-8, CCL5, IFN-beta and -lambda production. Furthermore, IFN-beta promoter activity (activated by poly I:C and RSV infection) was significantly reduced after treatment with CAM. CAM also inhibited IRF-3 dimerization and subsequent translocation to the nucleus. We conclude that CAM acts a crucial modulator of the innate immune response, particularly IFN production, by modulating IRF-3 dimerization and subsequent translocation to the nucleus of airway epithelial cells. This newly identified immunomodulatory action of CAM will facilitate the discovery of new macrolides with an anti-inflammatory role. (C) 2016 Elsevier Ltd. All rights reserved.