Altered sympathetic-to-immune cell signaling via β₂-adrenergic receptors in adjuvant arthritis

Clin Dev Immunol. 2013:2013:764395. doi: 10.1155/2013/764395. Epub 2013 Oct 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Agonists / administration & dosage
  • Adrenergic beta-2 Receptor Agonists / pharmacology
  • Animals
  • Arthritis, Experimental / drug therapy
  • Arthritis, Experimental / genetics
  • Arthritis, Experimental / immunology*
  • Arthritis, Experimental / metabolism*
  • Cyclic AMP / biosynthesis
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • G-Protein-Coupled Receptor Kinases / metabolism
  • Gene Expression
  • Interferon-gamma / biosynthesis
  • Lymph Nodes / drug effects
  • Lymph Nodes / immunology
  • Lymph Nodes / metabolism
  • Male
  • Phosphorylation
  • Protein Binding
  • Rats
  • Receptors, Adrenergic, beta-2 / genetics
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Severity of Illness Index
  • Signal Transduction*
  • Spleen / drug effects
  • Spleen / immunology
  • Spleen / metabolism
  • Sympathetic Nervous System / metabolism*
  • Sympathetic Nervous System / physiopathology
  • Terbutaline / administration & dosage
  • Terbutaline / pharmacology

Substances

  • Adrenergic beta-2 Receptor Agonists
  • Receptors, Adrenergic, beta-2
  • Interferon-gamma
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • G-Protein-Coupled Receptor Kinases
  • Terbutaline