title: Glycogen synthase kinase-3β modulation of glucocorticoid responsiveness in COPD.
abstract: In chronic obstructive pulmonary disease (COPD), oxidative stress regulates the inflammatory response of bronchial epithelium and monocytes/macrophages through kinase modulation and has been linked to glucocorticoid unresponsiveness. Glycogen synthase-3β (GSK3β) inactivation plays a key role in mediating signaling processes upon reactive oxygen species (ROS) exposure. We hypothesized that GSK3β is involved in oxidative stress-induced glucocorticoid insensitivity in COPD. We studied levels of phospho-GSK3β-Ser9, a marker of GSK3β inactivation, in lung sections and cultured monocytes and bronchial epithelial cells of COPD patients, control smokers, and nonsmokers. We observed increased levels of phospho-GSK3β-Ser9 in monocytes, alveolar macrophages, and bronchial epithelial cells from COPD patients and control smokers compared with nonsmokers. Pharmacological inactivation of GSK3β did not affect CXCL8 or granulocyte-macrophage colony-stimulating factor (GM-CSF) expression but resulted in glucocorticoid insensitivity in vitro in both inflammatory and structural cells. Further mechanistic studies in monocyte and bronchial epithelial cell lines showed that GSK3β inactivation is a common effector of oxidative stress-induced activation of the MEK/ERK-1/2 and phosphatidylinositol 3-kinase/Akt signaling pathways leading to glucocorticoid unresponsiveness. In primary monocytes, the mechanism involved modulation of histone deacetylase 2 (HDAC2) activity in response to GSK3β inactivation. In conclusion, we demonstrate for the first time that ROS-induced glucocorticoid unresponsiveness in COPD is mediated through GSK3β, acting as a ROS-sensitive hub.
authors: Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors: Anta
authors: http://orcid.org/0000-0002-0016-887X
authors: A
authors: Ngkelo
authors: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands;
authors: Roland F
authors: RF
authors: Hoffmann
authors: Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors: Andrew L
authors: AL
authors: Durham
authors: Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh Medical School, Edinburgh, United Kingdom;
authors: John A
authors: JA
authors: Marwick
authors: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands;
authors: Simone M
authors: SM
authors: Brandenburg
authors: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands;
authors: Harold G
authors: HG
authors: de Bruin
authors: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands;
authors: Marnix R
authors: MR
authors: Jonker
authors: Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors: Christos
authors: C
authors: Rossios
authors: Respiratory Research Group, Faculty of Medical and Human Sciences, University of Manchester, and National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester, Manchester, United Kingdom;
authors: Eleni
authors: E
authors: Tsitsiou
authors: Dipartimento di Scienze Mediche, Sezione di Medicina Interna e Cardiorespiratoria, Centro per lo Studio delle Malattie Infiammatorie Croniche delle Vie Aeree e Patologie Fumo Correlate dell'Apparato Respiratorio (formerly termed Centro di Ricerca su Asma e BPCO), Università di Ferrara, Ferrara, Italy;
authors: Gaetano
authors: G
authors: Caramori
authors: Dipartimento di Scienze Mediche, Sezione di Medicina Interna e Cardiorespiratoria, Centro per lo Studio delle Malattie Infiammatorie Croniche delle Vie Aeree e Patologie Fumo Correlate dell'Apparato Respiratorio (formerly termed Centro di Ricerca su Asma e BPCO), Università di Ferrara, Ferrara, Italy;
authors: Marco
authors: M
authors: Contoli
authors: Dipartimento di Scienze Mediche, Sezione di Medicina Interna e Cardiorespiratoria, Centro per lo Studio delle Malattie Infiammatorie Croniche delle Vie Aeree e Patologie Fumo Correlate dell'Apparato Respiratorio (formerly termed Centro di Ricerca su Asma e BPCO), Università di Ferrara, Ferrara, Italy;
authors: Paolo
authors: P
authors: Casolari
authors: Thoracic Surgery Unit, Cardiovascular and Thoracic Department, University of Messina, Messina, Italy;
authors: Francesco
authors: F
authors: Monaco
authors: Pneumology Unit, Cardiovascular and Thoracic Department, University of Messina, Italy;
authors: Filippo
authors: F
authors: Andò
authors: Department of Human Pathology "Gaetano Barresi," University of Messina, Messina, Italy;
authors: Giuseppe
authors: G
authors: Speciale
authors: Pfizer, Inflammation and Remodeling Research Unit, Cambridge, Massachusetts;
authors: Iain
authors: I
authors: Kilty
authors: Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors: Kian F
authors: KF
authors: Chung
authors: Dipartimento di Scienze Mediche, Sezione di Medicina Interna e Cardiorespiratoria, Centro per lo Studio delle Malattie Infiammatorie Croniche delle Vie Aeree e Patologie Fumo Correlate dell'Apparato Respiratorio (formerly termed Centro di Ricerca su Asma e BPCO), Università di Ferrara, Ferrara, Italy;
authors: Alberto
authors: A
authors: Papi
authors: Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, United Kingdom;
authors: Mark A
authors: MA
authors: Lindsay
authors: University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, The Netherlands; and University of Groningen, University Medical Center Groningen, Groningen, Groningen Research Institute for Asthma Research Institute, Groningen, The Netherlands.
authors: Nick H T
authors: NH
authors: Ten Hacken
authors: University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, The Netherlands; and University of Groningen, University Medical Center Groningen, Groningen, Groningen Research Institute for Asthma Research Institute, Groningen, The Netherlands.
authors: Maarten
authors: M
authors: van den Berge
authors: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Groningen, Groningen Research Institute for Asthma Research Institute, Groningen, The Netherlands.
authors: Wim
authors: W
authors: Timens
authors: Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors: Peter J
authors: PJ
authors: Barnes
authors: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Groningen, Groningen Research Institute for Asthma Research Institute, Groningen, The Netherlands.
authors: Antoon J
authors: AJ
authors: van Oosterhout
authors: Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; ian.adcock@imperial.ac.uk.
authors: Ian M
authors: http://orcid.org/0000-0003-2101-8843
authors: IM
authors: Adcock
authors: Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors: Paul A
authors: PA
authors: Kirkham
authors: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, The Netherlands; and University of Groningen, University Medical Center Groningen, Groningen, Groningen Research Institute for Asthma Research Institute, Groningen, The Netherlands.
authors: Irene H
authors: IH
authors: Heijink
mesh_terms: D000368:Aged; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000201:enzymology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000201:enzymology; D015398:Signal Transduction
chemical_list: D005938:Glucocorticoids; D017382:Reactive Oxygen Species; D003907:Dexamethasone; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2
keywords: COPD; epithelial cells; inflammatory responses; monocytes; oxidative stress