Nature Medicine
10, 1216 - 1221 (2004)
Published online: 24 October 2004; | doi:10.1038/nm1124
Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsisHong Wang1, 5, Hong Liao1, 5, Mahendar Ochani2, Marilou Justiniani1, Xinchun Lin3, Lihong Yang2, Yousef Al-Abed1, Haichao Wang4, Christine Metz1, Edmund J Miller3, Kevin J Tracey2
& Luis Ulloa11
The Center for Immunology and Inflammation, North Shore-LIJ Research Institute, North Shore University Hospital, 350 Community Drive, Manhasset, New York 11030, USA. 2
Center for Patient-Oriented Research, North Shore University Hospital, 350 Community Drive, Manhasset, New York 11030, USA. 3
Department of Surgery, North Shore University Hospital, 350 Community Drive, Manhasset, New York 11030, USA. 4
Department of Emergency Medicine, North Shore University Hospital, 350 Community Drive, Manhasset, New York 11030, USA. 5
These authors have contributed equally to this work.
Correspondence should be addressed to Luis Ulloa lulloa@nshs.eduPhysiological 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- ). Nicotinic stimulation prevents activation of the NF- B pathway and inhibits HMGB1 secretion through a specific 'nicotinic anti-inflammatory pathway' that requires the 7 nicotinic acetylcholine receptor (7nAChR). 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 7nAChR might have therapeutic potential for the treatment of sepsis.
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