beta-Agonist enhances type 2 T-cell survival and accumulation.
BACKGROUND
Neurohumoral modulation of immune system function is poorly understood. beta-Adrenergic receptor ligands (beta-agonists) subserve numerous physiologic processes but also function as pathogenic or therapeutic agents in numerous diseases with inflammatory components.


OBJECTIVE
We sought to establish the effects of beta-agonists and prostaglandin E(2) (PGE(2)) on antigen-dependent and antigen-independent accumulation of IL-13(+) (type 2) and IFN-gamma(+) (type 1) T cells. We also sought to clarify the mechanisms mediating the effects of these G protein-coupled receptor agonists.


METHODS
Effects of beta-agonists or PGE(2) on T-cell subtype accumulation were assessed in peripheral blood lymphocytes cultured with alphaCD3/CD28 or IL-2 by using flow cytometry. The role of cyclic AMP-dependent protein kinase (PKA) in mediating agonist effects was assessed by means of characterization of (1) phosphorylation of an intracellular PKA substrate and (2) T cells from patients with lupus possessing a natural defect in PKA activation.


RESULTS
beta-Agonists, in contrast to PGE(2), increased IL-2-induced accumulation of human type 2 T cells, an effect attributable to differential activation of PKA affecting regulation of cell proliferation and apoptosis. In T cells from patients with lupus exhibiting defective PKA activation, both beta-agonists and PGE(2) promoted an increase in type 2 T-cell accumulation.


CONCLUSIONS
G(s)-coupled receptors have the capacity to elicit prosurvival signaling in type 2 T cells, which, in most instances, is obscured by concomitant and antimitogenic PKA activation.


CONCLUSIONS
beta-Agonists and other G(s)-coupled receptor agonists have the potential to regulate T-cell development to affect disease pathogenesis or the efficacy of therapies, and variability of effect relates to the ability to stimulate PKA activity.
Loza
Matthew J
MJ
Department of Internal Medicine, Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Peters
Stephen P
SP
Foster
Susan
S
Khan
Islam U
IU
Penn
Raymond B
RB
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000276:immunology; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D018793:Interleukin-13 / Q000276:immunology; D007376:Interleukin-2 / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D000318:Adrenergic beta-Agonists; D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D018793:Interleukin-13; D007376:Interleukin-2; D007371:Interferon-gamma; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone; D007545:Isoproterenol