期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 119, 期 1, 页码 235-244出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2006.09.019
关键词
human; T cells; apoptosis; cytokines; signal transduction; beta-adrenergic receptor; prostaglandin E-2; EP receptor; lupus; asthma; heart failure; inflammation; cyclic AMP protein-dependent kinase
资金
- NCRR NIH HHS [M01-RR07122] Funding Source: Medline
- NHLBI NIH HHS [HL58506] Funding Source: Medline
- NIAMS NIH HHS [AR39501] Funding Source: Medline
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR007122] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL058506, R29HL058506] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR039501] Funding Source: NIH RePORTER
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. Objectives: 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 alpha CD3/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. Conclusion: 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. Clinical implications: 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.
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