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伊立替康（CPT-11），一种经典的抗癌药物，也能调节原代人滑膜成纤维细胞的抗病毒和促炎反应。

Irinotecan (CPT-11) Canonical Anti-Cancer Drug Can also Modulate Antiviral and Pro-Inflammatory Responses of Primary Human Synovial Fibroblasts.

作者信息

Dobi Anthony, Gasque Philippe, Guiraud Pascale, Selambarom Jimmy

机构信息

Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion (Site Félix Guyon), 97400 Saint-Denis, France.

Laboratoire d'Immunologie Clinique et Expérimentale de la Zone Océan Indien (LICE-OI), Pôle de Biologie, CHU de La Réunion (Site Félix Guyon), 97400 Saint-Denis, France.

出版信息

Cells. 2021 Jun 8;10(6):1431. doi: 10.3390/cells10061431.

DOI:10.3390/cells10061431
PMID:34201243
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8230279/
Abstract

Alphaviruses are a group of arboviruses that generate chronic inflammatory rheumatisms in humans. Currently, no approved vaccines or antiviral therapies are available to prevent or treat alphavirus-induced diseases. The aim of this study was to evaluate the repositioning of the anti-cancer molecule irinotecan as a potential modulator of the antiviral and inflammatory responses of primary human synovial fibroblasts (HSF), the main stromal cells of the joint synovium. HSF were exposed to O'nyong-nyong virus (ONNV) and polyinosinic-polycytidylic acid (PIC) to mimic, respectively, acute and chronic infectious settings. The cytokine IL-1β was used as a major pro-inflammatory cytokine to stimulate HSF. Quantitative RT-PCR analysis revealed that irinotecan at 15 µM was able to amplify the antiviral response (i.e., interferon-stimulated gene expression) of HSF exposed to PIC and reduce the expression of pro-inflammatory genes (CXCL8, IL-6 and COX-2) upon IL-1β treatment. These results were associated with the regulation of the expression of several genes, including those encoding for STAT1, STAT2, p53 and NF-κB. Irinotecan did not modulate these responses in both untreated cells and cells stimulated with ONNV. This suggests that this drug could be therapeutically useful for the treatment of chronic and severe (rather than acute) arthritis due to viruses.

摘要

甲病毒是一类虫媒病毒，可在人类中引发慢性炎症性风湿病。目前，尚无获批的疫苗或抗病毒疗法可用于预防或治疗甲病毒引起的疾病。本研究的目的是评估抗癌分子伊立替康重新定位为人类原发性滑膜成纤维细胞（HSF）抗病毒和炎症反应潜在调节剂的可能性，HSF是关节滑膜的主要基质细胞。分别用奥尼昂-尼昂病毒（ONNV）和聚肌苷酸-聚胞苷酸（PIC）处理HSF，以模拟急性和慢性感染情况。细胞因子IL-1β用作主要促炎细胞因子来刺激HSF。定量RT-PCR分析显示，15µM的伊立替康能够增强暴露于PIC的HSF的抗病毒反应（即干扰素刺激基因表达），并在IL-1β处理后降低促炎基因（CXCL8、IL-6和COX-2）的表达。这些结果与包括编码STAT1、STAT2、p53和NF-κB的基因在内的几个基因表达的调节有关。伊立替康在未处理的细胞和用ONNV刺激的细胞中均未调节这些反应。这表明该药物可能对治疗由病毒引起的慢性和重度（而非急性）关节炎具有治疗作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ddd/8230279/0bd0f8d05212/cells-10-01431-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ddd/8230279/f3c45dc27ea9/cells-10-01431-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ddd/8230279/4fd06eb48ccd/cells-10-01431-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ddd/8230279/65b1e68a8bf7/cells-10-01431-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ddd/8230279/99531eaecb53/cells-10-01431-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ddd/8230279/38b16287ae25/cells-10-01431-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ddd/8230279/0bd0f8d05212/cells-10-01431-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ddd/8230279/f3c45dc27ea9/cells-10-01431-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ddd/8230279/4fd06eb48ccd/cells-10-01431-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ddd/8230279/65b1e68a8bf7/cells-10-01431-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ddd/8230279/99531eaecb53/cells-10-01431-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ddd/8230279/38b16287ae25/cells-10-01431-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ddd/8230279/0bd0f8d05212/cells-10-01431-g006.jpg

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