Concurrent Agonism of Adenosine A_2Band Glucocorticoid Receptors in Human Airway Epithelial Cells Cooperatively Induces Genes with Anti-Inflammatory Potential: A Novel Approach to Treat Chronic Obstructive Pulmonary Disease

Abstract

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 A 2B -receptor subtype are efficacious in several cell-based assays and preclinical models of inflammation. Accordingly, the present study was designed to determine if a selective A 2B -receptor agonist, 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulphanyl]acetamide (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 cAMP-response element (CRE) and glucocorticoid response element (GRE) reporter constructs, Bay 60-6583 promoted CRE-dependent transcription and enhanced GRE-dependent transcription by an adenosine A 2B -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 categorized into genes that were induced in a positive cooperative manner (RGS2, p57 kip2 ), 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 A 2B -receptor agonist and a glucocorticoid administered together may have utility in the treatment of inflammatory disorders that respond suboptimally to glucocorticoids as a monotherapy.

Induction of Regulator of G-Protein Signaling 2 Expression by Long-Acting β2-Adrenoceptor Agonists and Glucocorticoids in Human Airway Epithelial Cells

“…This effect was mimicked by other cAMP-elevating agents, including the adenylyl cyclase activator forskolin, the PDE4 inhibitor rolipram, and PGE 2 , raising the prospect of additional therapeutic agents that could be usefully combined with a glucocorticoid. This is consistent with prior findings that these cAMP-elevating agents all enhance the activation of glucocorticoid-dependent transcription and that PDE inhibitors and adenosine A 2B agonists may enhance glucocorticoid-induced expression of multiple, potentially protective, genes including RGS2 Greer et al, 2013;Moodley et al, 2013).…”

CRISPLD2 Is a Target of Progesterone Receptor and Its Expression Is Decreased in Women with Endometriosis

“…This further supports a role for P4-PR in CRISPLD2 regulation in endometrium of both mice and humans. Additionally, the expression of CRISPLD2 is upregulated by glucocorticoid receptors on cultured airway smooth muscle cells [72] and upregulated by retinoic acid in myeloblastic leukemia cells (Gene Expression Omnibus (GEO) database GDS1215). PR, glucocorticoid receptors, and retinoic acid signaling pathways are relevant to uterine physiology and to the pathogenesis of endometriosis.…”

Glucocorticoids and the Lung

“…Thus, LGL1, although unlikely to be the primary mesenchymal factor that drives the effects of GR on the epithelium, exemplifi es the notion that secreted GR-regulated proteins in the mesenchyme can control epithelial development. Intriguingly, glucocorticoids induce the expression of LGL1 in Beas-2B airway epithelial cells [ 44 ].…”