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CRITICAL ROLE OF THE ALPHA-7 NICOTINIC ACETYLCHOLINE RECEPTOR IN THE DEVELOPMENT OF COLITIS
J-E Ghia, P Blennerhassett, AJ Park, Y Deng, R Cornell, SM Collins
Intestinal Diseases Research Programme, Health Science Center, McMaster University, Hamilton, Ontario
BACKGROUND AND AIMS: The anti-inflammatory reflex describes an interaction between the vagus nerve and the nicotinic receptors of peripheral macrophages, resulting in attenuation of pro-inflammatory cytokine release in response to exposure to dextran sulphate sodium (DSS). The aim of this study is to determine if the alpha-7 nicotinic acetylcholine receptor plays a critical role in the inflammatory responses in the colon in mice.
METHODS: We assessed disease activity index (DAI), macroscopic and histological damage, myeloperoxidase (MPO) activity, C-reactive protein and pro-inflammatory cytokines in colitis induced by administration of DSS, in healthy and vagotomized C57BL/6 and alpha-7 nicotinic acetylcholine receptor subunit-deficient mice. A pyloroplasty was performed in vagotomized mice.
RESULTS: DAI, macroscopic and histological scores MPO activity as well as levels of CRP and interleukin (IL)-1beta and IL-6 were significantly increased in alpha-7 deficient mice 5 days post-DSS induced colitis compared to control wild-type mice. Pre-treatment with nicotine (agonist) or choline-chloride (selective alpha-7 agonist) significantly decreased each of these markers in DSS-treated wild-type mice, but not in alpha-7 deficient mice treated with nicotine. Hexamethonium (antagonist) or methyllycaconitine (selective alpha-7 antagonist) treatment significantly increased each of these markers in the wild type mice DSS-treated, but not in alpha-7 deficient mice treated with hexamethonium. Vagotomy had no effect on the colitis in alpha-7 deficient mice.
CONCLUSIONS: These finding indicate that the vagus nerve plays a counter-inflammatory role in acute colitis via the nicotinic alpha-7 subunit receptors. The identification of new specific alpha-7 agonist opens new therapeutic avenues for treating acute exacerbations of inflammatory bowel disease.