The Journal of Experimental Medicine
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Published 4 April 2005. doi:10.1084/jem.20040463
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 7, 1113-1123
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ARTICLE

 Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation

Rubina W. Saeed1, Santosh Varma1,{dagger}, Tina Peng-Nemeroff1, Barbara Sherry2, David Balakhaneh3, Jared Huston4, Kevin J. Tracey4, Yousef Al-Abed3, and Christine N. Metz1

1 Laboratory of Medicinal Biochemistry, Institute for Medical Research at North Shore–LIJ, Manhasset, NY 11030
2 Laboratory of Chemokine Biology, Institute for Medical Research at North Shore–LIJ, Manhasset, NY 11030
3 Laboratory of Medicinal Chemistry, Institute for Medical Research at North Shore–LIJ, Manhasset, NY 11030
4 Laboratory of Biomedical Science, Institute for Medical Research at North Shore–LIJ, Manhasset, NY 11030

CORRESPONDENCE Christine N. Metz: cmetz{at}nshs.edu

Endothelial cell activation plays a critical role in regulating leukocyte recruitment during inflammation and infection. Based on recent studies showing that acetylcholine and other cholinergic mediators suppress the production of proinflammatory cytokines via the {alpha}7 nicotinic acetylcholine receptor ({alpha}7 nAChR) expressed by macrophages and our observations that human microvascular endothelial cells express the {alpha}7 nAChR, we examined the effect of cholinergic stimulation on endothelial cell activation in vitro and in vivo. Using the Shwartzman reaction, we observed that nicotine (2 mg/kg) and the novel cholinergic agent CAP55 (12 mg/kg) inhibit endothelial cell adhesion molecule expression. Using endothelial cell cultures, we observed the direct inhibitory effects of acetylcholine and cholinergic agents on tumor necrosis factor (TNF)-induced endothelial cell activation. Mecamylamine, an nAChR antagonist, reversed the inhibition of endothelial cell activation by both cholinergic agonists, confirming the antiinflammatory role of the nAChR cholinergic pathway. In vitro mechanistic studies revealed that nicotine blocked TNF-induced nuclear factor–{kappa}B nuclear entry in an inhibitor {kappa}B (I{kappa}B){alpha}- and I{kappa}B{varepsilon}-dependent manner. Finally, with the carrageenan air pouch model, both vagus nerve stimulation and cholinergic agonists significantly blocked leukocyte migration in vivo. These findings identify the endothelium, a key regulator of leukocyte trafficking during inflammation, as a target of anti-inflammatory cholinergic mediators.

Abbreviations used: ACh, acetylcholine; {alpha}-BGT, {alpha}-bungarotoxin; CAP55, cholinergic agonist P55; HRP, horseradish peroxidase; HuMVECs, human microvascular endothelial cells; ICAM-1, intercellular adhesion molecule 1; I{kappa}B, inhibitor {kappa}B; MCP-1, monocyte chemoattractant protein 1; MIP-1{alpha}, macrophage inflammatory protein 1{alpha}; MIP-1ß, macrophage inflammatory protein 1ß; MIP-2, macrophage inflammatory protein 2; nAChR, nicotinic acetylcholine receptor; VCAM-1, vascular cell adhesion molecule 1; VNS, vagus nerve stimulation.

R.W. Saeed and S. Varma contributed equally to this work.

{dagger} Dr. Varma died on 5 January 2004.


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