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 (RTqPCR). 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 downregulated 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

Relationships between Mucosal Antibodies, Non-Typeable Haemophilus influenzae (NTHi) Infection and Airway Inflammation in COPD

“…Among our NTHi isolates only one strain had the high expressing igaB allele and we observed no deficiency in IgA or sIgA in the NTHi+ve airway. Another reason for the observed decrease in IgG is suggested by a recent study demonstrating that inhaled steroids can inhibit both IgG gene expression and release[31]. However, we observed no difference in either the proportion of COPD patients taking inhaled steroids or the dose used between the infected and uninfected patients (Table 1).…”

Long-Actingβ2-Adrenoceptor Agonists Enhance Glucocorticoid Receptor (GR)–Mediated Transcription by Gene-Specific Mechanisms Rather Than Generic Effects via GR

“…Indeed, analysis of inflammatory gene expression suggests that GR transactivation operates alongside transrepression to produce repression (King et al, 2012). As many genes are induced in vivo in the human airways following ICS inhalation (Kelly et al, 2012;Leigh et al, 2016), or ICS/LABA inhalation (Lee et al, 2016), transcriptional activation most likely contributes to the clinical efficacy of these drugs.…”

Understanding how long‐acting β2‐adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma – an update

“…Importantly, many of these effector genes are up‐regulated by LABA and/or glucocorticoids in primary human ASM cells (Misior et al , ). Furthermore, the fact that the expression of many such genes is increased in the human airways following budesonide inhalation, as well as in COPD patients taking inhaled fluticasone propionate/salmeterol, supports the concept that such effects are therapeutically relevant and may be enhanced in the presence of a LABA (Kelly et al , ; Lee et al , ; Leigh et al , ).…”