title: Glucocorticoids reduce inflammation in cystic fibrosis bronchial epithelial cells.
abstract: Reduction of lung inflammation is one of the goals of cystic fibrosis (CF) therapy. Among anti-inflammatory molecules, glucocorticoids (GC) are one of the most prescribed. However, CF patients seem to be resistant to glucocorticoid treatment. Several molecular mechanisms that contribute to decrease anti-inflammatory effects of glucocorticoids have been identified in pulmonary diseases, but the molecular actions of glucocorticoids have never been studied in CF. In the cytoplasm, glucocorticoids bind to glucocorticoid receptor (GR) and then, control NF-κB and MAPK pathways through direct interaction with AP-1 and NF-κB in the nucleus. Conversely, MAPK can regulate glucocorticoid activation by targeting GR phosphorylation. Together these pathways regulate IL-8 release in the lung. Using bronchial epithelial cell lines derived from non CF and CF patients, we analyzed GR-based effects of glucocorticoids on NF-κB and MAPK pathways, after stimulation with TNF-α. We demonstrate that the synthetic glucocorticoid dexamethasone (Dex) significantly decreases IL-8 secretion, AP-1 and NF-κB activity in CF cells in a pro-inflammatory context. Moreover, we show that p38 MAPK controls IL-8 release by determining GR activation through specific phosphorylation on serine 211. Finally, we demonstrate a synergistic effect of dexamethasone treatment and inhibition of p38 MAPK inducing more than 90% inhibition of IL-8 production in CF cells. All together, these results demonstrate the good responsiveness to glucocorticoids of CF bronchial epithelial cells and the reciprocal link between glucocorticoids and p38 MAPK in the control of CF lung inflammation.
authors.affiliation: UPMC Univ Paris 06, Paris F-75012, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Rebeyrol
authors.forename: Vinciane
authors.initials: V
authors.lastname: Saint-Criq
authors.forename: Loïc
authors.initials: L
authors.lastname: Guillot
authors.forename: Laure
authors.initials: L
authors.lastname: Riffault
authors.forename: Harriet
authors.initials: H
authors.lastname: Corvol
authors.forename: Katarina
authors.initials: K
authors.lastname: Chadelat
authors.forename: David W
authors.initials: DW
authors.lastname: Ray
authors.forename: Annick
authors.initials: A
authors.lastname: Clement
authors.forename: Olivier
authors.initials: O
authors.lastname: Tabary
authors.forename: Philippe
authors.initials: P
authors.lastname: Le Rouzic
mesh_terms: D000841:Anisomycin / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D055745:Bronchioles / Q000473:pathology*; D002460:Cell Line; D003550:Cystic Fibrosis / Q000473:pathology*; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation; D016209:Interleukin-8 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C508606:CXCL8 protein, human; D005938:Glucocorticoids; D016209:Interleukin-8; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D000841:Anisomycin; D003907:Dexamethasone; D048051:p38 Mitogen-Activated Protein Kinases