Chronic obstructive pulmonary disease (COPD) is a neutrophilic inflammatory disorder that is weakly responsive to glucocorticoids. Identification of ways to enhance the anti-inflammatory activity of glucocorticoids is, therefore, a major research objective. Adenosine receptor agonists that target the A2B-receptor-subtype are efficacious in several cell-based assays and pre-clinical models of inflammation. Accordingly, the present study was designed to determine if a selective A2B-receptor agonist, Bay 60-6583, and a glucocorticoid, dexamethasone in combination display putative anti-inflammatory activity that is superior to either drug alone. In BEAS-2B human airway epithelial cells stably transfected with CRE and GRE reporter constructs, Bay 60-6583 promoted CRE-dependent transcription and enhanced GRE-dependent transcription by adenosine A2B-receptor-mediated mechanism that was associated with cAMP formation and abolished by an inhibitor of cAMP-dependent protein kinase. Analysis of the concentration-response relationship that described the enhancement of GRE-dependent transcription showed that Bay 60-6583 increased the magnitude of response without affecting the potency of dexamethasone. Bay 60-6583 and dexamethasone also induced a panel of genes that, collectively, could have benefit in COPD. These were categorised into genes that were induced in a positive cooperative manner (RGS2, p57kip2), an additive manner (TTP, BRL-1) or by Bay 60-6583 (CD200, CRISPLD2, SOCS3) or dexamethasone (GILZ) only. Thus, the gene induction "fingerprints" produced by Bay 60-6583 and dexamethasone, alone and in combination, were distinct. Collectively, through their actions on gene expression, an adenosine A2B-receptor agonist and a glucocorticoid administered together may have utility in the treatment of inflammatory disorders that respond sub-optimally to glucocorticoids as a monotherapy.
- adenosine receptors
- chronic obstructive pulmonary disease
- epithelial cells
- respiratory pharmacology
- The American Society for Pharmacology and Experimental Therapeutics