title: Clarithromycin prevents human respiratory syncytial virus-induced airway epithelial responses by modulating activation of interferon regulatory factor-3.
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.
authors.affiliation: Department of Otorhinolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Soh
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Otorhinolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan. Electronic address: ogasawara.n@sapmed.ac.jp.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ogasawara
authors.affiliation: Department of Otorhinolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Takano
authors.affiliation: Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Shiraishi
authors.affiliation: Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Toyotaka
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Otorhinolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Miyata
authors.affiliation: Department of Otorhinolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kakuki
authors.affiliation: Department of Otorhinolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Kamekura
authors.affiliation: Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
authors.affiliation: Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsumi
authors.affiliation: Department of Otorhinolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Himi
authors.affiliation: Department of Microbiology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Yokota
mesh_terms: D000072283:A549 Cells; D021581:Active Transport, Cell Nucleus; D017291:Clarithromycin / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007155:Immunologic Factors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D055503:Protein Multimerization; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000187:drug effects* / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D014162:Transfection
chemical_list: C494232:IRF3 protein, human; D007155:Immunologic Factors; D018836:Inflammation Mediators; D050838:Interferon Regulatory Factor-3; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D007372:Interferons; D017291:Clarithromycin
keywords: Airway epithelial cells; Clarithromycin (PubChem CID: 84029); IRF-3; Innate immunity; Interferon; Macrolide; Pam3CSK4 (PubChem CID: 130704); poly I:C (PubChem CID: 32744)