Dr. Janssen owns stock options in Galapagos.
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Rheumatoid Arthritis Basic Science Studies
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The α7 nicotinic acetylcholine receptor on fibroblast-like synoviocytes and in synovial tissue from rheumatoid arthritis patients: A possible role for a key neurotransmitter in synovial inflammation
Article first published online: 29 APR 2009
DOI: 10.1002/art.24470
Copyright © 2009 by the American College of Rheumatology
Additional Information
How to Cite
Maanen, M. A. V., Stoof, S. P., Zanden, E. P. V. D., Jonge, W. J. D., Janssen, R. A., Fischer, D. F., Vandeghinste, N., Brys, R., Vervoordeldonk, M. J. and Tak, P. P. (2009), The α7 nicotinic acetylcholine receptor on fibroblast-like synoviocytes and in synovial tissue from rheumatoid arthritis patients: A possible role for a key neurotransmitter in synovial inflammation. Arthritis & Rheumatism, 60: 1272–1281. doi: 10.1002/art.24470
Publication History
- Issue published online: 29 APR 2009
- Article first published online: 29 APR 2009
- Manuscript Accepted: 31 JAN 2009
- Manuscript Received: 10 JUL 2008
Funded by
- Top Institute Pharma. Grant Number: T1-215
- Netherlands Organization for Scientific Research (grants NWO and VIDI)
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Abstract
Objective
Recent studies have suggested an important role for neurotransmitters as modulators of inflammation. Therefore, we undertook this study to investigate the expression of the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR) and its function in rheumatoid arthritis (RA).
Methods
The potential role of the α7nAChR in modulating proinflammatory cytokine expression in fibroblast-like synoviocytes (FLS) was identified by screening an adenoviral short hairpin RNA (Ad.shRNA) library. An α7-specific antibody was used for immunohistochemistry, and fluorescein isothiocyanate–labeled α-bungarotoxin, which binds specifically to the α7nAChR, was used for immunofluorescence. Gene expression in FLS was determined by quantitative polymerase chain reaction with primers specific for the α7nAChR. In addition, we analyzed messenger RNA (mRNA) expression of dupα7, a variant α7 transcript. Next, we studied the functional role of the α7nAChR in RA FLS by examining the effects of α7-specific agonists on the production of interleukin-6 (IL-6) and IL-8 by activated FLS.
Results
A screen using an Ad.shRNA library against 807 transcripts revealed that a specific α7nAChR shRNA potently modulated IL-8 and matrix metalloproteinase expression in FLS. The α7nAChR was expressed in the inflamed synovium from RA patients, predominantly in the intimal lining layer. We found α7nAChR expression at both the mRNA and protein level in cultured RA FLS. FLS also constitutively expressed dupα7 mRNA. Specific α7nAChR agonists reduced tumor necrosis factor α–induced IL-6 and IL-8 production by FLS.
Conclusion
The α7nAChR and its dupα7 variant are expressed in RA synovium, where they may play a critical role in regulating inflammation. Targeting the α7nAChR could provide a novel antiinflammatory approach to the treatment of RA.