Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis.

Journal Article (Journal Article)

Physiological anti-inflammatory mechanisms can potentially be exploited for the treatment of inflammatory disorders. Here we report that the neurotransmitter acetylcholine inhibits HMGB1 release from human macrophages by signaling through a nicotinic acetylcholine receptor. Nicotine, a selective cholinergic agonist, is more efficient than acetylcholine and inhibits HMGB1 release induced by either endotoxin or tumor necrosis factor-alpha (TNF-alpha). Nicotinic stimulation prevents activation of the NF-kappaB pathway and inhibits HMGB1 secretion through a specific 'nicotinic anti-inflammatory pathway' that requires the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). In vivo, treatment with nicotine attenuates serum HMGB1 levels and improves survival in experimental models of sepsis, even when treatment is started after the onset of the disease. These results reveal acetylcholine as the first known physiological inhibitor of HMGB1 release from human macrophages and suggest that selective nicotinic agonists for the alpha7nAChR might have therapeutic potential for the treatment of sepsis.

Full Text

Duke Authors

Cited Authors

  • Wang, H; Liao, H; Ochani, M; Justiniani, M; Lin, X; Yang, L; Al-Abed, Y; Wang, H; Metz, C; Miller, EJ; Tracey, KJ; Ulloa, L

Published Date

  • November 2004

Published In

Volume / Issue

  • 10 / 11

Start / End Page

  • 1216 - 1221

PubMed ID

  • 15502843

Pubmed Central ID

  • 15502843

International Standard Serial Number (ISSN)

  • 1078-8956

Digital Object Identifier (DOI)

  • 10.1038/nm1124

Language

  • eng

Conference Location

  • United States