title: Beclomethasone dipropionate and formoterol reduce oxidative/nitrosative stress generated by cigarette smoke extracts and IL-17A in human bronchial epithelial cells.
abstract: Interleukin-17A (IL-17A), cigarette smoke and oxidative/nitrosative stress are involved in inflammatory airway diseases, and the mechanisms behind these processes are still poorly understood. We investigated whether recombinant human IL-17A (rhIL-17A), in combination with cigarette smoke extracts (CSE), increases the levels of inducibile nitric oxide synthase (iNOS), reactive oxygen species, nitrotyrosine (NT) and the activation of signal transducer and activator of transcription 1 (STAT-1) in normal human bronchial epithelial cells (16HBE). The effect of beclomethasone dipropionate (BDP), formoterol and their combination was also evaluated. We demonstrated that rhIL-17A or CSE alone increases iNOS expression, reactive oxygen species and NT production and STAT-1 downstream signalling activation in terms of STAT-1ser727 and STAT-1tyr701 phosphorylation. The combination of both stimuli further increased iNOS, ROS, NT and STAT-1ser727 phosphorylation. The silencing of STAT-1 expression partially reduced the levels of iNOS, reactive oxygen species and NT generated by rhIL-17A and inhibited the effect of CSE alone in 16HBE cells. The treatment of the cells with the MEK1/2 inhibitor U0126 (1,4-diamino-2,3-dicyano-1,4-bis (o-aminophenylmercapto butadiene) abolished the expression of iNOS and STAT-1ser727 phosphorylation generated by rhIL-17A. 16HBE treated with BDP or formoterol alone partially suppressed the effect of IL-17A or CSE on ROS, NT, and STAT-1 activation. Furthermore the use of the drugs in combination showed an additive effect in 16HBE. Our findings demonstrate that IL-17A increases oxidative/nitrosative markers, likely via ERK1/2 downstream signalling and STAT-1 pathway activation in human bronchial epithelial cells. BDP and formoterol treatment reduces this effect showing an additive effect used in combination.
authors: Institute of Biomedicine and Molecular Immunology (IBIM), Italian National Research Council (CNR), Palermo, Italy.
authors: Angela Marina
authors: AM
authors: Montalbano
authors: Giulia
authors: G
authors: Anzalone
authors: Giusy Daniela
authors: GD
authors: Albano
authors: Caterina Di
authors: CD
authors: Sano
authors: Rosalia
authors: R
authors: Gagliardo
authors: Anna
authors: A
authors: Bonanno
authors: Loredana
authors: L
authors: Riccobono
authors: Gabriele
authors: G
authors: Nicolini
authors: Eleonora
authors: E
authors: Ingrassia
authors: Mark
authors: M
authors: Gjomarkaj
authors: Mirella
authors: M
authors: Profita
mesh_terms: D001507:Beclomethasone / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D001980:Bronchi / Q000166:cytology; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*; D062789:Tobacco Products / Q000009:adverse effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D015415:Biomarkers; D002070:Butadienes; D004983:Ethanolamines; D020381:Interleukin-17; D009570:Nitriles; D026361:Reactive Nitrogen Species; D050794:STAT1 Transcription Factor; D012906:Smoke; C113580:U 0126; D052247:Nitric Oxide Synthase Type II; D001507:Beclomethasone; D000068759:Formoterol Fumarate
keywords: Cigarette smoke; Epithelial cells; Interleukin-17A (IL-17A); Oxidative/nitrosative stress