Corticosteroids and β2 Agonists Differentially Regulate Rhinovirus-induced Interleukin-6 via Distinct Cis-acting Elements

Abstract

Interleukin-6 (IL-6) is a proinflammatory cytokine up-regulated by rhinovirus infection during acute exacerbations of asthma and chronic obstructive pulmonary disease. The role of IL-6 during exacerbations is unclear; however, it is believed IL-6 could contribute to airway and systemic inflammation. In this study we investigate the effects of common asthma treatments fluticasone propionate and ␤ 2 agonists salmeterol and salbutamol on IL-6 production in BEAS-2B and primary bronchial epithelial cells. Salmeterol and salbutamol enhanced rhinovirus-and IL-1␤-induced IL-6 production; however, fluticasone treatment caused a reduction of IL-6 protein and mRNA. Combined activity of salmeterol and fluticasone at equimolar concentrations had no effect on rhinovirus or IL-1␤ induction of IL-6. The induction of IL-6 by salmeterol was dependent upon the ␤ 2 receptor and could also be induced by cAMP or cAMPelevating agents forskolin and rolipram. Using transfection of IL-6 promoter reporter constructs, dominant negative mutants, and electromobility shift assays, it was found that NF-B was the only transcription factor required for rhinovirus induction of IL-6 gene expression. Salmeterol caused an augmentation of rhinovirus-induced promoter activation via a mechanism dependent upon the c/EBP and/or CRE (cyclic AMP response element) cis-acting sites. The suppressive effect of FP was dependent upon distinct glucocorticoid response element sequences proximal to the transcriptional start site within the IL-6 promoter. The data demonstrate that ␤ 2 agonists can augment IL-6 expression by other stimuli in an additive manner via cyclic AMP and that the negative effect of steroids is mediated by glucocorticoid response elements within the IL-6 promoter.

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

“…We first chose FP at 10 −9  mol/L (1 nmol/L) as this concentration is approximately the EC 50 for these cytokines in bronchial epithelial models (Edwards et al. 2007, 2006), and FP has been found at approximately this concentration in lung tissue following inhalation (Esmailpour et al. 1997).…”

Childhood asthma and infection: virus-induced exacerbations as determinants and modifiers

“…Pharmacological interventions shown to be relatively successful at preventing asthma exacerbations include inhaled corticosteroids and their combination with long lasting b 2 -agonists (mostly in adults), leukotriene modifiers and anti-immunoglobulin E therapy [8,[94][95][96][97]. Corticosteroids suppress eosinophilic inflammation through various pathways [98,99]. However, the inability of corticosteroids to modulate several other aspects of the immune response to respiratory viruses that lead to asthma exacerbations make them not as effective at preventing or treating virus-induced asthma exacerbations in different age groups [100].…”

Effect of different asthma treatments on risk of cold-related exacerbations

“…In pooled clinical trials, fewer cold-related exacerbations occurred with salmeterol/ fluticasone than with fluticasone alone [13]. Further insights into the differences seen in the present analyses have been obtained from in vitro studies, which have shown a dose-dependent reduction in rhinovirus-induced interleukin (IL)-6, IL-8, C-C ligand (CCL)5 (a lymphocyte chemokine) and CXC ligand (CXCL)8 (a neutrophil attractor/activator) when airway epithelial cells were pre-treated with corticosteroids [10,11,32]. Pre-treatment with corticosteroids also abolished rhinovirusinduced loss of b 2 -receptor function [33].…”

“…Pre-treatment with corticosteroids also abolished rhinovirusinduced loss of b 2 -receptor function [33]. Salmeterol enhanced rhinovirus-induced IL-6 production [11], which may contribute to the adverse effects of LABA monotherapy [34], but salmeterol/fluticasone downregulated CCL5 and CXCL8 mRNA and protein expression at significantly lower concentrations than fluticasone alone, suggesting a synergistic effect [10].…”

“…Asthma clinical trials only rarely document causes of exacerbations and few include viral sampling, so information about therapeutic effects during clinical colds is largely limited to in vitro rhinovirus studies [10][11][12]. However, adverse events (AEs), including clinical colds, are prospectively recorded at study visits with a standardised question such as ''Have you had any health problems since your last visit?''…”