title: Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling.
abstract: 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 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 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, 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 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 with saline-treated endotoxemic controls. Choline also suppressed HMGB1 release in vitro and in vivo, and choline treatment initiated 24 h 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.
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York 11030, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Parrish
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rosas-Ballina
authors.forename: Margot
authors.initials: M
authors.lastname: Gallowitsch-Puerta
authors.forename: Mahendar
authors.initials: M
authors.lastname: Ochani
authors.forename: Kanta
authors.initials: K
authors.lastname: Ochani
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Yang
authors.forename: LaQueta
authors.initials: L
authors.lastname: Hudson
authors.forename: Xinchun
authors.initials: X
authors.lastname: Lin
authors.forename: Nirav
authors.initials: N
authors.lastname: Patel
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Johnson
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Chavan
authors.forename: Richard S
authors.initials: RS
authors.lastname: Goldstein
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Czura
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Miller
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: Valentin A
authors.initials: VA
authors.lastname: Pavlov
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D002794:Choline / Q000494:pharmacology* / Q000502:physiology*; D019446:Endotoxemia / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D004731:Endotoxins / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000893:Anti-Inflammatory Agents; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D004731:Endotoxins; D024243:HMGB1 Protein; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; D002794:Choline