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

Catalina Marysol Carvajal Gonczi; Fadi Touma; Tina Daigneault; Chelsea Pozzebon; Kelly Burchell-Reyes; Peter J. Darlington; Catalina Marysol Carvajal Gonczi; Fadi Touma; Tina Daigneault; Chelsea Pozzebon; Kelly Burchell-Reyes; Peter J. Darlington

doi:10.3934/Allergy.2021017

AIMS Allergy and Immunology

2021, Volume 5, Issue 4: 222-239. doi: 10.3934/Allergy.2021017

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Research article Topical Sections

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

1.
Clinical Analysis Laboratory, PERFORM Centre, Department of Biology, Concordia University, Montreal, QC, Canada
2.
Faculty of Medicine, University of Toronto, Toronto, ON, Canada
3.
Faculty of Medicine and Health Sciences, McGill University, Montréal, QC, Canada
4.
Department of Chemistry, University of Laval, Québec City, QC, Canada
5.
Clinical Analysis Laboratory, PERFORM Centre, Department of Health, Kinesiology & Applied Physiology, Department of Biology, Concordia University, Montreal, QC, Canada

Received: 16 July 2021 Accepted: 13 October 2021 Published: 18 October 2021

Background
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 ADRB2. 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 ADRB2 polymorphisms on IL-17A and IFNγ responses.
Methods
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 in vitro. Cytokines IL-17A and IFNγ were measured using enzyme-linked immunosorbent assay. Genomic ADRB2 and its immediate upstream region were sequenced using Sanger's method. Cytokine response to drug was analyzed based on ADRB2 polymorphisms.
Results
Terbutaline consistently inhibited IFNγ from activated PBMC samples. In contrast, it increased IL-17A in PBMC homozygous for Gly16 codon of ADRB2. 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 ADRB2 polymorphisms.
Conclusions
This data demonstrates that terbutaline inhibited IFNγ, however, it increased IL-17A in samples with the common Gly16 polymorphism of ADRB2. Nebivolol inhibited IL-17A regardless of ADRB2 polymorphisms. Thus, nebivolol is a strong candidate for treating inflammatory diseases or disorders where IL-17A exacerbates symptoms.
- β2-adrenergic receptor,
- helper T cells,
- terbutaline,
- nebivolol,
- cytokines
Citation: Catalina Marysol Carvajal Gonczi, Fadi Touma, Tina Daigneault, Chelsea Pozzebon, Kelly Burchell-Reyes, Peter J. Darlington. Modulation of IL-17A and IFNγ by β2-adrenergic agonist terbutaline and inverse-agonist nebivolol, influence of ADRB2 polymorphisms[J]. AIMS Allergy and Immunology, 2021, 5(4): 222-239. doi: 10.3934/Allergy.2021017

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Abstract

Background

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 ADRB2. 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 ADRB2 polymorphisms on IL-17A and IFNγ responses.

Methods

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 in vitro. Cytokines IL-17A and IFNγ were measured using enzyme-linked immunosorbent assay. Genomic ADRB2 and its immediate upstream region were sequenced using Sanger's method. Cytokine response to drug was analyzed based on ADRB2 polymorphisms.

Results

Terbutaline consistently inhibited IFNγ from activated PBMC samples. In contrast, it increased IL-17A in PBMC homozygous for Gly16 codon of ADRB2. 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 ADRB2 polymorphisms.

Conclusions

This data demonstrates that terbutaline inhibited IFNγ, however, it increased IL-17A in samples with the common Gly16 polymorphism of ADRB2. Nebivolol inhibited IL-17A regardless of ADRB2 polymorphisms. Thus, nebivolol is a strong candidate for treating inflammatory diseases or disorders where IL-17A exacerbates symptoms.

Acknowledgments

We thank the contribution of Pierre Lepage, Sebastien Brunet, and Philippe Daoust of the McGill University and Génome Québec Innovation Centre, Montréal, Canada for Sanger sequencing. This work was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery grants (grant numbers RGPIN-418522-2013 and RGPIN-2019-06980).

Conflict of interest

All authors declare no conflicts of interest in this paper.

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