Modulation of TNF Release by Choline Requires Alpha7 Subunit Nicotinic Acetylcholine Receptor-Mediat
June 29th, 2008 | by admin |Modulation of TNF Release by Choline Requires Alpha7 Subunit Nicotinic Acetylcholine Receptor-Mediated Signaling.
The alpha7 subunit-containing nicotinic acetylcholine receptor (alpha7nAChR) is an essential component in the vagus nerve-based \”cholinergic anti-inflammatory pathway\” that regulates the levels of TNF, high mobility group box1 (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 alpha7nAChR agonist. Here we studied the anti-inflammatory potential of choline in murine endotoxemia and sepsis and the role of the alpha7nAChR 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-kappaB activation. Choline (50 mg/kg, 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 alpha7nAChR knockout mice during endotoxemia. Choline also failed to suppress TNF release from endotoxin-activated peritoneal macrophages isolated from alpha7nAChR knockout mice. Choline treatment prior to endotoxin resulted in a significantly improved survival rate as compared to saline-treated endotoxemic controls. Choline also suppressed HMGB1 release in vitro and in vivo and choline treatment initiated 24h after 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 alpha7nAChR-mediated signaling.
Parrish WR, Rosas-Ballina M, Gallowitsch-Puerta M, Ochani M, Ochani K, Hudson LQ, Lin X, Patel N, Johnson SM, Chavan S, Goldstein R, Czura CJ, Miller EJ, Al-Abed Y, Tracey KJ, Pavlov VA.
Laboratory of Biomedical Science.