Published ahead of print on February 2, 2006, doi:10.1165/rcmb.2005-0196OC
© 2006 American Thoracic Society DOI: 10.1165/rcmb.2005-0196OC Eosinophil-Mediated Cholinergic Nerve RemodelingDepartment of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland; Department of Pharmacology, University of Liverpool; Division of Therapeutics and Molecular Medicine, University of Nottingham; Department of Medicine, Queen's University of Belfast, United Kingdom; Department of Neurology and Neuroscience, Boston University, Boston, Massachusetts; Department of Dermatology, University of Utah, Salt Lake City, Utah; and Department of Clinical Pharmacology, University of Malta, Msida, Malta Correspondence and requests for reprints should be addressed to Marie-Therese Walsh, Department of Medicine, RCSI, Beaumont Hospital, Dublin 9, Ireland. E-mail: mtwalsh{at}rcsi.ie Eosinophils are observed to localize to cholinergic nerves in a variety of inflammatory conditions such as asthma, rhinitis, eosinophilic gastroenteritis, and inflammatory bowel disease, where they are also responsible for the induction of cell signaling. We hypothesized that a consequence of eosinophil localization to cholinergic nerves would involve a neural remodeling process. Eosinophil co-culture with cholinergic IMR32 cells led to increased expression of the M2 muscarinic receptor, with this induction being mediated via an adhesion-dependent release of eosinophil proteins, including major basic protein and nerve growth factor. Studies on the promoter sequence of the M2 receptor indicated that this induction was initiated at a transcription start site 145 kb upstream of the gene-coding region. This promoter site contains binding sites for a variety of transcription factors including SP1, AP1, and AP2. Eosinophils also induced the expression of several cholinergic genes involved in the synthesis, storage, and metabolism of acetylcholine, including the enzymes choline acetyltransferase, vesicular acetylcholine transferase, and acetylcholinesterase. The observed eosinophil-induced changes in enzyme content were associated with a reduction in intracellular neural acetylcholine but an increase in choline content, suggesting increased acetylcholine turnover and a reduction in acetylcholinesterase activity, in turn suggesting reduced catabolism of acetylcholine. Together these data suggest that eosinophil localization to cholinergic nerves induces neural remodeling, promoting a cholinergic phenotype.
Key Words: cholinergic • eosinophil • muscarinic • asthma This article has been cited by other articles:
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