Azithromycin augments rhinovirus-induced expression of IFNβ and IFNλ1 in asthmatic bronchial epithelial cells by up-regulating RIG-I like receptors

Rationale: Macrolides exhibit antiviral and anti-inflammatory properties and are potential treatments of asthma exacerbations. Impaired production of interferons has been described in viral-induced exacerbations of asthma. Using primary human bronchial epithelial cells (HBECs) from asthmatic donors we investigate effects of azithromycin on rhinovirus-induced IFNβ and IFNλ1 as well as on potentially involved RIG-I like receptors (RLR). Methods: HBECs were obtained from bronchial brushing during fiberbronchoscopy from patients with atopic asthma. HBECs were pretreated with azithromycin (0.4-25 µM) for 24h prior to infection with rhinovirus RV16 (1 MOI). Cells and supernatant were harvested 8h, 24h and 48h after RV16 infection for subsequent gene (RT-qPCR) or protein expression (ELISA and WB) analysis. Results: RV16 infection alone induced expression of IFNλ1 and IFNβ, which was further augmented 3-5fold (p<0.01) by azithromycin in a dose-dependent manner. This response was closely associated with increased RIG-I and MDA5 expression (p<0.01). Induction of interferons seems to be two-phase, an early augmentation at 8h and a later one at 24h which was sustained until 56h post-infection. Early interferon response was accompanied by an up-regulation of RLRs and a trend at induction of TLR3. Conclusions: Azithromycin induced RLRs and type I and III interferons in rhinovirus-infected asthmatic HBECs. We suggest that up-regulation of RLRs and increased expression of antiviral proteins by azithromycin would be a desirable action in the treatment of rhinovirus infection-evoked asthma exacerbations but needs to be confirmed in vivo.