The β2-adrenergic receptor agonist terbutaline upregulates T helper-17 cells in a protein kinase A-dependent manner

• Published in: Human immunology Vol. 84; no. 10; pp. 515 - 524
• Main Authors: Carvajal Gonczi, Catalina M., Hajiaghayi, Mehri, Gholizadeh, Fatemeh, Xavier Soares, Maria Auxiliadora, Touma, Fadi, Lopez Naranjo, Carolina, Rios, Amanda J., Pozzebon, Chelsea, Daigneault, Tina, Burchell-Reyes, Kelly, Darlington, Peter J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2023
• Subjects: Beta-2-adrenergic receptor; CD4; IL-17A; Memory T cells; Terbutaline; IL-17A; PKA; Memory T cells; cAMP; PBMC; Th cells; g-protein; Terbutaline; IFN; AR; CD4; CREB; ROR; FBS; Beta-2-adrenergic receptor; ELISA
• ISSN: 0198-8859; 1879-1166
• DOI: 10.1016/j.humimm.2023.06.007

T helper 17 (Th17) cells produce IL-17A cytokine and can exacerbate autoimmune diseases and asthma. The β2 adrenergic receptor is a g protein-coupled receptor that induces cAMP second messenger pathways. We tested the hypothesis that terbutaline, a β2-adrenergic receptor-specific agonist, promotes IL-17 secretion by memory Th17 cells in a cAMP and PKA-dependent manner. Venous peripheral blood mononuclear cells (PBMC) from healthy human participants were activated with anti-CD3 and anti-CD28 antibodies. Secreted IL-17A was measured by enzyme linked immunosorbent assay, intracellular IL-17A, and RORγ were measured using flow cytometry, and RORC by qPCR. Memory CD3+CD4+CD45RA-CD45RO+ T cells were obtained by immunomagnetic negative selection and activated with tri-antibody complex CD3/CD28/CD2. Secreted IL-17A, intracellular IL-17A, RORC were measured, and phosphorylated-serine133-CREB was measured by western blotting memory Th cells. Terbutaline increased IL-17A (p < 0.001), IL-17A+ cells (p < 0.05), and RORC in activated PBMC and memory Th cells. The PKA inhibitors H89 (p < 0.001) and Rp-cAMP (p < 0.01) abrogated the effects of terbutaline on IL-17A secretion in PBMC and memory T cells. Rolipram increased IL-17A (p < 0.01) to a similar extent as terbutaline. P-Ser133-CREB was increased by terbutaline (p < 0.05) in memory T cells. Terbutaline augments memory Th17 cells in lymphocytes from healthy participants. This could exacerbate autoimmune diseases or asthma, in cases where Th17 cells are considered to be pro-inflammatory.