Modulation of IL-17A and IFNγ by β2-adrenergic agonist terbutaline and inverse-agonist nebivolol, influence of ADRB2 polymorphisms

Abstract

<abstract><sec> <title>Background</title> <p>Upon activation, helper T (Th) cells produce cytokines such as IL-17A and IFNγ, which may exacerbate inflammatory disease and disorders. Adrenergic drugs are emerging as immunomodulatory agents to treat pro-inflammatory diseases, but their function is not completely understood. Th Cells express the β2-adrenergic receptor (β2AR) that is encoded by <italic>ADRB2</italic>. Agonists of the β2AR decrease IFNγ but can increase IL-17A from Th cells. We compared a β2AR agonist to an inverse-agonist, and assessed the influence of <italic>ADRB2</italic> polymorphisms on IL-17A and IFNγ responses.</p> </sec><sec> <title>Methods</title> <p>Peripheral blood mononuclear cells (PBMCs) from venous blood of healthy human participants were cultured with T cell activators anti-CD3 and anti-CD28 antibodies. Terbutaline, a β2AR agonist or nebivolol, a β1AR antagonist and β2AR inverse-agonist, were added <italic>in vitro</italic>. Cytokines IL-17A and IFNγ were measured using enzyme-linked immunosorbent assay. Genomic <italic>ADRB2</italic> and its immediate upstream region were sequenced using Sanger's method. Cytokine response to drug was analyzed based on <italic>ADRB2</italic> polymorphisms.</p> </sec><sec> <title>Results</title> <p>Terbutaline consistently inhibited IFNγ from activated PBMC samples. In contrast, it increased IL-17A in PBMC homozygous for Gly16 codon of <italic>ADRB2</italic>. Nebivolol inhibited IL-17A and IFNγ from activated Th cells. When applied to activated-PBMCs, nebivolol inhibited IL-17A but did not significantly inhibit IFNγ although a trend was observed. The ability of nebivolol to inhibit IL-17A was attenuated by a β2AR-specific antagonist. Cellular proliferation and viability was not significantly changed by nebivolol. Nebivolol suppressed IL-17A in all of the samples regardless of <italic>ADRB2</italic> polymorphisms.</p> </sec><sec> <title>Conclusions</title> <p>This data demonstrates that terbutaline inhibited IFNγ, however, it increased IL-17A in samples with the common Gly16 polymorphism of <italic>ADRB2</italic>. Nebivolol inhibited IL-17A regardless of <italic>ADRB2</italic> polymorphisms. Thus, nebivolol is a strong candidate for treating inflammatory diseases or disorders where IL-17A exacerbates symptoms.</p> </sec></abstract>