Reduced glucocorticoid receptor expression and function in airway neutrophils.
Chronic Obstructive Pulmonary Disease (COPD) is a glucocorticoid resistant condition characterised by airway neutrophilia. Reduced glucocorticoid receptor (GR) expression in COPD airway neutrophils may be a mechanism that contributes to glucocorticoid resistance. Our objective was to investigate the expression and function of GR within COPD airway neutrophils. Dual-label immunofluorescence was used to analyse airway neutrophil expression of GR within peripheral lung tissue samples (11 COPD patients, 7 healthy non-smokers [NS]) and induced sputum (7 COPD patients, 7 NS). TNFα and CXCL8 release were measured in neutrophils isolated from induced sputum and peripheral blood (7 COPD patients) in the presence of dexamethasone. In lung tissue, GR was abundantly expressed in macrophages and lymphocytes, but very low expression was observed in neutrophils (means 6.8% and 4.3% in COPD patients and NS respectively). Similarly low expression was observed in sputum neutrophils (means 3.8% and 6.9% in COPD patients and NS respectively). In contrast, GR was expressed by 100% of blood neutrophils. Dexamethasone had less suppressive effect on TNFα and CXCL8 production in vitro by neutrophils from induced sputum compared to neutrophils from paired blood samples. Airway neutrophils have low expression of GR in both COPD patients and controls. The effects of glucocorticoids on cytokine production from airway neutrophils are reduced. Increased numbers of airway neutrophils lacking GR may contribute to glucocorticoid resistance in COPD patients.
University of Manchester, NIHR Translational Research Facility, Manchester Academic Health Science Centre, University Hospital of South Manchester, Manchester, UK. Jonathan.plumb@manchester.ac.uk
Jonathan
J
Plumb
Kate
K
Gaffey
Binita
B
Kane
Brendan
B
Malia-Milanes
Rajesh
R
Shah
Andrew
A
Bentley
David
D
Ray
Dave
D
Singh
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology; D007958:Leukocyte Count; D008168:Lung / Q000166:cytology / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000276:immunology*; D011965:Receptors, Glucocorticoid / Q000276:immunology*; D013183:Sputum / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D055815:Young Adult
C508606:CXCL8 protein, human; D005938:Glucocorticoids; D016209:Interleukin-8; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone