title: AP-1 overexpression impairs corticosteroid inhibition of collagen production by fibroblasts isolated from asthmatic subjects.
abstract: Asthma is characterized by airway remodeling associated with an increase in the deposition of ECM proteins such as type I collagen. These components are mainly produced by fibroblasts. Inhaled corticosteroids are considered the cornerstone of asthma therapy. Despite substantial evidence as to the anti-inflammatory action of corticosteroids, their effect on controlling ECM protein deposition in the airways is not completely understood. This study determined the effect of dexamethasone (Dex) on collagen production by bronchial fibroblasts derived from asthmatic and healthy subjects. Expression of procollagen mRNA in fibroblasts from asthmatics and normal controls was determined by quantitative PCR. Regulation of the procollagen-alpha(1)I promoter was evaluated by transient transfections. Transforming growth factor-beta (TGF-beta) protein expression was determined by ELISA. Protein expression of glucocorticoid receptor (GR) and interaction with activator protein-1 (AP-1), a collagen regulatory transcription factor, was assessed by Western blots, coimmunoprecipitations, and EMSA. AP-1 overexpression was performed by transient transfection using c-Fos/c-Jun expression plasmids. Dex significantly downregulated procollagen production and promoter activity in normal fibroblasts but had no effect on asthmatic fibroblasts. AP-1 and GR interaction increased after Dex stimulation in asthmatic fibroblasts. AP-1 overexpression in control fibroblasts abrogated collagen gene response to Dex. These results show that Dex failed to reduce collagen production in fibroblasts from asthmatic subjects. This impaired response may be related to AP-1 overexpression in these cells.
authors.affiliation: Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie, Sainte-Foy, Québec, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Jacques
authors.forename: Abdelhabib
authors.initials: A
authors.lastname: Semlali
authors.forename: Louis Philippe
authors.initials: LP
authors.lastname: Boulet
authors.forename: Jamila
authors.initials: J
authors.lastname: Chakir
mesh_terms: D000328:Adult; D056151:Airway Remodeling / Q000187:drug effects; D001249:Asthma / Q000378:metabolism*; D001980:Bronchi / Q000378:metabolism; D024042:Collagen Type I / Q000096:biosynthesis*; D000090602:Collagen Type I, alpha 1 Chain; D003907:Dexamethasone / Q000494:pharmacology*; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D003907:Dexamethasone