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

Abstract	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.
Authors	Hong Wang, Hong Liao, Mahendar Ochani, Marilou Justiniani, Xinchun Lin, Lihong Yang, Yousef Al-Abed, Haichao Wang, Christine Metz, Edmund J Miller, Kevin J Tracey, Luis Ulloa
Journal	Nature medicine (Nat Med) Vol. 10 Issue 11 Pg. 1216-21 (Nov 2004) ISSN: 1078-8956 [Print] United States
PMID	15502843 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Chrna7 protein, human Chrna7 protein, mouse HMGB1 Protein Lipopolysaccharides Oligonucleotides Receptors, Nicotinic alpha7 Nicotinic Acetylcholine Receptor Nicotine Acetylcholine
Topics	Acetylcholine (agonists, metabolism) Animals Cecum (injuries) Fluorescent Antibody Technique HMGB1 Protein (antagonists & inhibitors, blood, metabolism) Humans Inflammation (metabolism) Lipopolysaccharides Macrophages (metabolism) Mice Neuroimmunomodulation (physiology) Nicotine (metabolism, therapeutic use) Oligonucleotides Receptors, Nicotinic (metabolism) Sepsis (drug therapy, metabolism) Signal Transduction (physiology) alpha7 Nicotinic Acetylcholine Receptor

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!