Clarithromycin prevents human respiratory syncytial virus-induced airway epithelial responses by modulating activation of interferon regulatory factor-3. (September 2016)

• Record Type: Journal Article
• Authors: Yamamoto, Keisuke; Yamamoto, Soh; Ogasawara, Noriko; Takano, Kenichi; Shiraishi, Tsukasa; Sato, Toyotaka; Miyata, Ryo; Kakuki, Takuya; Kamekura, Ryuta; Kojima, Takashi; Tsutsumi, Hiroyuki; Himi, Tetsuo; Yokota, Shin-ichi
• Is Part Of: Pharmacological research. Volume 111(2016:Sep.)
• Page Start: 804
• Page End: 814
• Publication Date: 2016-09
• Subjects: Clarithromycin (PubChem CID: 84029) -- poly I:C (PubChem CID: 32744) -- Pam3CSK4 (PubChem CID: 130704); CAM clarithromycin -- CARD caspase activation and recruitment domain -- CCL5 chemokine (C-C motif) ligand 5 -- CF cystic fibrosis -- COPD chronic obstructive pulmonary disease -- DAPI, 4′, 6-diamino-2-phenylindole DMSO dimethylsulfoxide -- DPB diffuse panbronchiolitis -- ERK extracellular signal-regulated kinase -- hTERT-HNEC human telomerase reverse transcriptase-transfected human nasal epithelial cells -- IFN interferon -- IKK I kappa B-related kinases -- IL interleukin -- IRF interferon regulatory factor -- LRI lower respiratory tract illness -- mAb monoclonal antibody -- MAPK mitogen-activated protein kinase -- MAVS mitochondrial antiviral-signaling protein -- MDA-5 melanoma differentiation-associated gene 5 -- MOI multiplicity of infection -- MuV mumps virus -- NF-κB nuclear factor-kappa B -- NOD nucleotide binding oligomerization domain -- PBS phosphate-buffered saline -- poly I:C polyinosinic-polycytidylic acid -- PRR pattern recognition receptor -- RIG-I retinoic acid-inducible gene-I -- RLR RIG-I-like receptors -- RSV human respiratory syncytial virus -- STAT signal transducer and activator of transcription -- TBK-1 TANK-binding kinase 1 -- TIR Toll/interleukin-1 receptor -- TLR Toll-like receptor -- TNF-α tumor necrosis factor-α -- TRIF TIR-domain-containing adapter-inducing interferon-β -- TRAF tumor necrosis factor receptor-associated factor -- TSLP thymic stromal lymphopoietin; Macrolide -- Innate immunity -- Interferon -- IRF-3 -- Airway epithelial cells; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2016.07.033
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: 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-β and -λ production. Furthermore, IFN-β 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.