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Modulation of Helper T Cells by β2 Adrenergic Receptor Ligands in a PKA-Dependent Manner


Modulation of Helper T Cells by β2 Adrenergic Receptor Ligands in a PKA-Dependent Manner

Carvajal Gonczi, Catalina Marysol (2020) Modulation of Helper T Cells by β2 Adrenergic Receptor Ligands in a PKA-Dependent Manner. PhD thesis, Concordia University.

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Modulation of Helper T Cells by β2 Adrenergic Receptor Ligands in a PKA-Dependent Manner

Catalina Marysol Carvajal Gonczi, Ph.D
Concordia University, 2020

Background: T helper (Th) cells may attack self-tissues in susceptible people resulting in chronic autoimmune disease. A subtype of Th cells called Th17 cells are considered to be pro-inflammatory by secreting IL-17A cytokines. Discovering new drugs to suppress Th17 cells is a major goal for researchers. Ligands for the beta2-adrenergic receptor (β2AR, encoded by ADRB2) are known to suppress pro-inflammatory Th1 cells, but their effects on Th17 cells have not been widely studied. I studied the effect of β2AR ligands on Th1 and Th17 cells and determined the influence of common polymorphisms ADRB2. The goal was to discover a potential new immunomodulatory drug to explore as autoimmune disease treatment.
Methods: Human immune cells from healthy participants obtained after informed consent were tested in vitro. The samples were activated with T cell-specific activator, and cytokines were measured. The in vitro drug treatments included a β2AR specific agonist (terbutaline), an inverse-agonist (nebivolol), a β2AR specific antagonist (ICI 118-551), cAMP analogues that promote or inhibit the pathway, PKA inhibitor and phosphodiesterase inhibitor (which raises cAMP levels). Known polymorphisms were determined by sequencing ADRB2 from samples.
Results: Primary human Th17 cells expressed the β2AR. Terbutaline augmented IL-17A in activated peripheral blood mononuclear cells and Th17 cells, while IFNγ was concurrently inhibited. Proliferation was not inhibited, rather, an increase was observed in the presence of terbutaline. Using PKA inhibitors and cAMP analogues, it was shown that IL-17A was augmented by terbutaline in a cAMP and PKA-dependent manner. Terbutaline promoted phosphorylation of CREB. Nebivolol inhibited both IL-17A and IFNγ in activated peripheral blood mononuclear cells and Th cells. In samples where ADRB2 was homozygous for Arg16, terbutaline inhibited IFNγ but did not augment IL-17A. Nebivolol inhibited both cytokines regardless of the polymorphism of the ADRB2.
Relevance: These results are novel because the inverse-agonist of β2AR has not been widely studied as an immunomodulator. The cell signalling results demonstrated that Th17 cells respond differently than other Th cells to cAMP-PKA pathway, which suggests the use of other drugs with inverse-agonist properties. Discovering new immunomodulatory drugs will give doctors more options to treat autoimmune patients.

Divisions:Concordia University > Faculty of Arts and Science > Biology
Item Type:Thesis (PhD)
Authors:Carvajal Gonczi, Catalina Marysol
Institution:Concordia University
Degree Name:Ph. D.
Date:July 2020
Thesis Supervisor(s):Darlington, Peter
ID Code:987967
Deposited By: Catalina Marysol Carvajal
Deposited On:29 Jun 2021 21:00
Last Modified:29 Jun 2021 21:00


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