Macrolides inhibit IL17-induced IL8 and 8-isoprostane release from human airway smooth muscle cells

Lung transplantation is hampered by bronchiolitis obliterans syndrome (BOS), although recently azithromycin treatment has a published response rate of about 42% in patients with established BOS. We linked this improvement to a reduction in airway neutrophilia and IL8. In the present study, we further investigated the intracellular mechanisms of azithromycin, looking at the possible involvement of mitogen-activated-protein kinases (MAPK) and oxidative stress. Simultaneously, currently used immunosuppressive agents were investigated. Human primary airway smooth muscle cells were stimulated with IL17 and incubated with increasing concentrations of steroids, immunosuppressive agents (tacrolimus, cyclosporine and rapamycin) or macrolides (erythromycin and azithromycin). We measured supernatant IL8 protein, 8-isoprostane and cell lysate MAPK. IL17-induced IL8 production was decreased by both erythromycin and azithromycin. In nonstimulated condition, IL8 production only increased at the highest dose of azithromycin. Dexamethasone failed to attenuate IL8 production, whereas immunosuppressive agents significantly increased IL8 production in both IL17-stimulated and nonstimulated conditions. 8-isoprostane production and MAPK activation proved to be decreased by the macrolides. We conclude that macrolides (but not steroids/immunosuppressive agents) inhibit IL17-induced IL8 production in human primary airway smooth muscle cells via a reduction in MAPK activation and 8-isoprostane production. In BOS patients, these phenomena may explain the anti-inflammatory effects of azithromycin.