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1 Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
2 Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
* To whom correspondence should be addressed. E-mail: w.g.mclean{at}liv.ac.uk.
One immunological component of asthma is believed to be the interaction of eosinophils with parasympathetic cholinergic nerves and a consequent inhibition of acetylcholine muscarinic M2 receptor activity, leading to enhanced acetylcholine release and bronchoconstriction. Here we have used an in vitro model of cholinergic nerve function - the human IMR32 cell line - to study this interaction. IMR32 cells, differentiated in culture for 7 days, expressed M2 receptors. Cells were radiolabelled with [3H]-choline and electrically stimulated. The stimulation-induced release of acetylcholine was prevented by the removal of Ca++. The muscarinic M1/M2 receptor agonist arecaidine reduced the release of acetylcholine after stimulation (to 82 ± 2% of control at 10-7 M) and the M2 receptor antagonist AF-DX 116 increased it (to 175 ±23% of control at 10-5 M), indicating the presence of a functional M2 receptor that modulated acetylcholine release. When human eosinophils were added to IMR32 cells they enhanced acetylcholine release by 36 ± 10%. This effect was prevented by inhibitors of adhesion of the eosinophils to the IMR32 cells. Pre-treatment of IMR32 cells with 10 mM carbachol, to desensitise acetylcholine receptors, prevented the potentiation of acetylcholine release by eosinophils or AF-DX 116. Acetylcholine release was similarly potentiated (by up to 45 ±7%) by degranulation products from eosinophils that had been treated with fMLP or had been in contact with IMR32 cells. Contact between eosinophils and IMR32 cells led to an initial increase in expression of M2 receptors, while prolonged exposure reduced M2 receptor expression.
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