β ₂ -Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids

Abstract

In asthma and chronic obstructive pulmonary disease, activation of G q -protein-coupled receptors causes bronchoconstriction. In each case, the management of moderate-to-severe disease uses inhaled corticosteroid (glucocorticoid)/long-acting β 2 -adrenoceptor agonist (LABA) combination therapies, which are more efficacious than either monotherapy alone. In primary human airway smooth muscle cells, glucocorticoid/LABA combinations synergistically induce the expression of regulator of G-protein signaling 2 (RGS2), a GTPaseactivating protein that attenuates G q signaling. Functionally, RGS2 reduced intracellular free calcium flux elicited by histamine, methacholine, leukotrienes, and other spasmogens. Furthermore, protection against spasmogen-increased intracellular free calcium, following treatment for 6 h with LABA plus corticosteroid, was dependent on RGS2. Finally, Rgs2-deficient mice revealed enhanced bronchoconstriction to spasmogens and an absence of LABA-induced bronchoprotection. These data identify RGS2 gene expression as a genomic mechanism of bronchoprotection that is induced by glucocorticoids plus LABAs in human airway smooth muscle and provide a rational explanation for the clinical efficacy of inhaled corticosteroid (glucocorticoid)/LABA combinations in obstructive airways diseases.adrenoreceptor | beta-2-adrenergic receptor | protein kinase A | glucocorticoid receptor | NR3C1

Asthma control in adult patients treated with a combination of inhaled corticosteroids and long-acting beta-2 agonists: a prospective observational study

“…Optimal patient reported asthma control was translocation of the activated glucocorticoid re ceptor complex to the cell nucleus, thereby in creasing steroid induced transcriptional activi ty. 1,2,4 This finding proves the usefulness of com bining ICS and LABA treatments. There is also some compelling evidence that it is even more useful to combine these treatments in a single inhaler, as discussed below.…”

“…First of all, a combination of LABAs and ICSs shows syner gistic activity. 4 Glucocorticoids influence the β 2 adrenoceptor expression and inhibit its func tional desensitization, while β 2 agonists induce in primary care, allergy, and respiratory medicine clinics throughout Poland. The study involved 886 physicians and 11 270 patients.…”

Glucocorticoid and TNF signaling converge at A20 (TNFAIP3) to repress airway smooth muscle cytokine expression

“…These include genes that primarily affect noninflammatory pathways such as CD38, an NF-B target that increases ASM contractility and is repressed by GCs (25,29,59), and RGS2 (66), whose induction by GR is similarly implicated in modulating ASM contraction (25). In addition, a host of genes with presumptive proinflammatory activity such as IL6, CCL2, and RANTES, among others, are potently repressed in ASM by steroid treatment (2,45).…”

Superiority of Combined Phosphodiesterase PDE3/PDE4 Inhibition over PDE4 Inhibition Alone on Glucocorticoid- and Long-Acting β2-Adrenoceptor Agonist–Induced Gene Expression in Human Airway Epithelial Cells

“…The relative cDNA concentration of target genes was derived from parallel analysis of a standard curve of serially diluted cDNA. Amplification primers for RGS2, cluster of differentiation 200 (CD200), cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2), DUSP1, and GAPDH were as described and the specificity of the primers was determined by dissociation (melt) curve analysis (King et al, 2009;Holden et al, 2011;Moodley et al, 2013).…”

“…Western blotting and adenoviral infections were carried out as previously described (King et al, 2009;Holden et al, 2011). Primary antibodies were glyceraldehyde-3-phosphate dehydrogenase (GAPDH) ] (AbD Serotec, Raleigh, NC), cAMP response element-binding protein (CREB) (9197), and phospho-CREB (9191) (Cell Signaling Technology, Danvers, MA).…”