Genomic effects of an EP4-receptor agonist in airway epithelia

It has been proposed that inhaled EP4-receptor agonists could represent an alternative class of bronchodilators for the treatment of asthma that are as effective as β2-adrenoceptor agonists. However, the genomic impact of such drugs is often overlooked despite being potentially deleterious to respiratory health. Herein, we used mRNA-seq to compare the genomic impact of ONO-AE1-329 (an EP4-receptor agonist) and vilanterol (a β2-adrenoceptor agonist) in BEAS-2B human airway epithelial cells. We also determined if an increase in cAMP mediated by different GPCRs promoted distinct transcriptional signatures by expanding this enquiry to include the adenosine A2B- and I-prostanoid receptor agonists, Bay-60-6583 and taprostene, respectively. Maximally-effective concentrations of ONO-AE1-329 and vilanterol significantly regulated (q ≤ 0.05; ≥1.5-/≤0.67-fold) 232 and 320 genes, respectively of which 217 were shared. Spearman analysis showed these gene expression changes to be highly rank order correlated indicating that the functional overlap between the two interventions should be considerable. Unexpectedly, the genomic effects of ONO-AE1-329, vilanterol, Bay 60-6583 and taprostene were also highly rank order correlated. This finding raises the prospect that cAMP generated by any GPCR would initiate the same transcriptional program. Nevertheless, relative to vilanterol, ONO-AE1-329 typically behaved as a partial agonist with a potency and intrinsic activity that varied across transcripts. Collectively, this investigation demonstrated that each ONO-AE1-329-regulated gene differs in sensitivity to cAMP and is defined by a unique receptor occupancy-response relationship. Moreover, if this relatively modest genomic response in BEAS-2B cells is reproduced in vivo, then inhaled EP4-receptor agonists could represent a safer class of bronchodilators.