title: Altered sympathetic-to-immune cell signaling via β₂-adrenergic receptors in adjuvant arthritis.
abstract: Adjuvant-induced arthritic (AA) differentially affects norepinephrine concentrations in immune organs, and in vivo β-adrenergic receptor (β-AR) agonist treatment distinctly regulates ex vivo cytokine profiles in different immune organs. We examined the contribution of altered β-AR functioning in AA to understand these disparate findings. Twenty-one or 28 days after disease induction, we examined β₂-AR expression in spleen and draining lymph nodes (DLNs) for the arthritic limbs using radioligand binding and western blots and splenocyte β-AR-stimulated cAMP production using enzyme-linked immunoassay (EIA). During severe disease, β-AR agonists failed to induce splenocyte cAMP production, and β-AR affinity and density declined, indicating receptor desensitization and downregulation. Splenocyte β₂-AR phosphorylation (pβ₂-AR) by protein kinase A (pβ₂-AR(PKA)) decreased in severe disease, and pβ₂-AR by G protein-coupled receptor kinases (pβ₂-AR(GRK)) increased in chronic disease. Conversely, in DLN cells, pβ₂-AR(PKA) rose during severe disease, but fell during chronic disease, and pβ₂-AR(GRK) increased during both disease stages. A similar pβ₂-AR pattern in DLN cells with the mycobacterial cell wall component of complete Freund's adjuvant suggests that pattern recognition receptors (i.e., toll-like receptors) are important for DLN pβ₂-AR patterns. Collectively, our findings indicate lymphoid organ- and disease stage-specific sympathetic dysregulation, possibly explaining immune compartment-specific differences in β₂-AR-mediated regulation of cytokine production in AA and rheumatoid arthritis.
authors.affiliation: Hoover Arthritis Research Center, Banner Health Research Institute, 10515 W. Santa Fe Drive, Sun City, AZ 85351, USA ; Department of Psychology, Kent State University, 133 Kent Hall, Kent, OH 44242, USA ; Kent-Summa Institute for Clinical and Translational Research, Summa Health System, 525 East Market Street, Akron,OH 44304, USA.
authors.forename: Dianne
authors.initials: D
authors.lastname: Lorton
authors.forename: Denise L
authors.initials: DL
authors.lastname: Bellinger
authors.forename: Jill A
authors.initials: JA
authors.lastname: Schaller
authors.forename: Eric
authors.initials: E
authors.lastname: Shewmaker
authors.forename: Tracy
authors.initials: T
authors.lastname: Osredkar
authors.forename: Cheri
authors.initials: C
authors.lastname: Lubahn
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism; D015870:Gene Expression; D007371:Interferon-gamma / Q000096:biosynthesis; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism* / Q000503:physiopathology; D013726:Terbutaline / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2; D007371:Interferon-gamma; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054768:G-Protein-Coupled Receptor Kinases; D013726:Terbutaline