Journal
MOLECULAR MEDICINE
Volume 14, Issue 9-10, Pages 567-574Publisher
FEINSTEIN INST MED RES
DOI: 10.2119/2008-00079.Parrish
Keywords
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Funding
- North Shore-LIJ Health System Research Award
- NIGMS [R01 GM0557226-08A1]
- [MO1 R018535]
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The alpha 7 subunit-containing nicotinic acetylcholine receptor (alpha 7nAChR) is an essential component in the vagus nerve-based cholinergic anti-inflammatory pathway that regulates the levels of TNF, high mobility group box 1 (HMGB1), and other cytokines during inflammation. Choline is an essential nutrient, a cell membrane constituent, a precursor in the biosynthesis of acetylcholine, and a selective natural alpha 7nAChR agonist. Here, we studied the anti-inflammatory potential of choline in murine endotoxemia and sepsis, and the role of the alpha 7nAChR in mediating the suppressive effect of choline on TNF release. Choline (0.1-50 mM) dose-dependently suppressed TNF release from endotoxin-activated RAW macrophage-like cells, and this effect was associated with significant inhibition of NF-kappa B activation. Choline (50 mg/kg, intraperitoneally (i.p.)) treatment prior to endotoxin administration in mice significantly reduced systemic TNF levels, In contrast to its TNF suppressive effect in wild type mice, choline (50 mg/kg, i.p.) failed to inhibit systemic TNF levels in alpha 7nAChR knockout mice during endotoxemia. Choline also failed to suppress TNF release from endotoxin-activated peritoneal macrophages isolated from alpha 7nAChR knockout mice, Choline treatment prior to endotoxin resulted in a significantly improved survival rate as compared with saline-treated endotoxemic controls. Choline also suppressed HMGB1 release in vitro and in vivo, and choline treatment initiated 24 h aft er cecal ligation and puncture (CLP)-induced polymicrobial sepsis significantly improved survival in mice. in addition, choline suppressed TNF release from endotoxin-activated human whole blood and macrophages. Collectively, these data characterize the anti-inflammatory efficacy of choline and demonstrate that the modulation of TNF release by choline requires alpha 7nAChR-mediated signaling.
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