title: Corticosteroid modulation of immunoglobulin expression and B-cell function in COPD.
abstract: We investigated changes in gene expression that occur in chronic obstructive pulmonary disease (COPD) after corticosteroid treatment and sought to identify the mechanisms that regulate these changes. Biopsy samples were taken from patients with COPD (Global Initiative for Chronic Obstructive Lung Disease stage I to II) before and after treatment with fluticasone propionate (FP)/salmeterol (SM) (50/500, 4 wk). Gene expression was measured by microarray and was confirmed by real-time reverse transcription-quantitative PCR (RT-qPCR). The effect of FP on IgG expression and B-cell proliferation in the presence of oxidative stress was also studied. FP/SM significantly increased the expression of 180 genes while repressing 343 genes. The top 5 down-regulated genes were associated with immunoglobulin production, whereas the immunomodulatory FK506 binding protein (FK506BP) was up-regulated. Genes including IL6, IL8, and TBET-encoding TBX21 were unaffected. FP reduced IgG protein and mRNA expression and proliferation of human B cells through the dephosphorylation of ERK-1/2 via increased DUSP1 (dual-specificity protein phosphatase 1) expression. Consistent with in vivo data, oxidative stress did not prevent FP-induced suppression of IgG expression in human B cells in vitro Changes in expression were validated by RT-qPCR and by gene set enrichment analysis in distinct COPD cohorts. FP may reduce the adaptive immune response in COPD and may be more effective in patients with an increased B-cell/antibody response indicated by high autoantibody titers.-Lee, J., Machin, M., Russell, K. E., Pavlidis, S., Zhu, J., Barnes, P. J., Chung, K. F., Adcock, I. M., Durham, A. L. Corticosteroid modulation of immunoglobulin expression and B-cell function in COPD.
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
authors.forename: Jin
authors.initials: J
authors.lastname: Lee
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
authors.forename: Matthew
authors.initials: M
authors.lastname: Machin
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
authors.forename: Kirsty E
authors.initials: KE
authors.lastname: Russell
authors.affiliation: Janssen Research and Development, High Wycombe, United Kingdom.
authors.forename: Stelios
authors.initials: S
authors.lastname: Pavlidis
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
authors.forename: Kian F
authors.initials: KF
authors.lastname: Chung
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and a.durham@imperial.ac.uk.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Durham
mesh_terms: D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D000068297:Fluticasone-Salmeterol Drug Combination / Q000008:administration & dosage / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D010865:Pilot Projects; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D001993:Bronchodilator Agents; C504459:FILIP1L protein, human; D000068297:Fluticasone-Salmeterol Drug Combination; D005938:Glucocorticoids; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins
keywords: DUSP1; ERK; LABA; fluticasone propionate