Whole blood cytokine attenuation by cholinergic agonists ex vivo and relationship to vagus nerve activity in rheumatoid arthritis

J Intern Med. 2010 Jul;268(1):94-101. doi: 10.1111/j.1365-2796.2010.02226.x. Epub 2010 Feb 18.


Objective: The central nervous system regulates innate immunity in part via the cholinergic anti-inflammatory pathway, a neural circuit that transmits signals in the vagus nerve that suppress pro-inflammatory cytokine production by an alpha-7 nicotinic acetylcholine receptors (alpha7nAChR) dependent mechanism. Vagus nerve activity is significantly suppressed in patients with autoimmune diseases, including rheumatoid arthritis (RA). It has been suggested that stimulating the cholinergic anti-inflammatory pathway may be beneficial to patients, but it remains theoretically possible that chronic deficiencies in this pathway will render these approaches ineffective.

Methods: Here we addressed the hypothesis that inflammatory cells from RA patients can respond to cholinergic agonists with reduced cytokine production in the setting of reduced vagus nerve activity.

Results: Measurement of RR interval variability (heart rate variability, HRV), in RA patients (n = 13) and healthy controls (n = 10) revealed that vagus nerve activity was significantly depressed in patients. Whole blood cultures stimulated by exposure to endotoxin produced significantly less tumour necrosis factor in samples from RA patients as compared to healthy controls. Addition of cholinergic agonists (nicotine and GTS-21) to the stimulated whole blood cultures however significantly suppressed cytokine production to a similar extent in patients and healthy controls.

Conclusion: These findings suggest that it is possible to pharmacologically target the alpha7nAChR dependent control of cytokine release in RA patients with suppressed vagus nerve activity. As alpha7nAChR agonists ameliorate the clinical course of collagen induced arthritis in animals, it may be possible in the future to explore whether alpha7nAChR agonists can improve clinical activity in RA patients.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / physiopathology*
  • Benzylidene Compounds / pharmacology
  • C-Reactive Protein / analysis
  • Case-Control Studies
  • Cholinergic Agonists / pharmacology*
  • Cytokines / biosynthesis
  • Cytokines / blood*
  • Dose-Response Relationship, Immunologic
  • Female
  • HMGB1 Protein / blood
  • Heart Rate / physiology
  • Humans
  • Lipopolysaccharides / immunology
  • Male
  • Middle Aged
  • Nicotine / pharmacology
  • Prospective Studies
  • Pyridines / pharmacology
  • Receptors, Nicotinic / drug effects
  • Tissue Culture Techniques
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Vagus Nerve / physiopathology*
  • alpha7 Nicotinic Acetylcholine Receptor


  • Benzylidene Compounds
  • Cholinergic Agonists
  • Chrna7 protein, human
  • Cytokines
  • HMGB1 Protein
  • Lipopolysaccharides
  • Pyridines
  • Receptors, Nicotinic
  • Tumor Necrosis Factor-alpha
  • alpha7 Nicotinic Acetylcholine Receptor
  • Nicotine
  • 3-(2,4-dimethoxybenzylidene)anabaseine
  • C-Reactive Protein