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PMID: 15809354 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation.

The Journal of experimental medicine ·Vol. 201 ·No. 7 ·2005-04-04 ·Pages 1113-23

Saeed RW, Varma S, Peng-Nemeroff T, Sherry B, Balakhaneh D, Huston J, Tracey KJ, Al-Abed Y, Metz CN

Abstract

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 alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) expressed by macrophages and our observations that human microvascular endothelial cells express the alpha7 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-kappaB nuclear entry in an inhibitor kappaB (IkappaB)alpha- and IkappaBepsilon-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.

MeSH Terms
Acetylcholine/pharmacology Animals Blotting, Western Carrageenan Cell Adhesion Molecules/antagonists & inhibitors,metabolism Cell Migration Inhibition Cholinergic Agents/pharmacology DNA Primers Endothelial Cells/drug effects,metabolism Enzyme-Linked Immunosorbent Assay Female Flow Cytometry Humans Inflammation/immunology,metabolism Leukocytes/immunology Mecamylamine/pharmacology Mice Mice, Inbred BALB C Nicotine/pharmacology Nicotinic Antagonists Phagocytes/immunology,metabolism Receptors, Nicotinic/metabolism Reverse Transcriptase Polymerase Chain Reaction Shwartzman Phenomenon/immunology Tumor Necrosis Factor-alpha/metabolism Vagus Nerve/metabolism alpha7 Nicotinic Acetylcholine Receptor
Chemicals
Cell Adhesion Molecules Cholinergic Agents Chrna7 protein, human Chrna7 protein, mouse DNA Primers Nicotinic Antagonists Receptors, Nicotinic Tumor Necrosis Factor-alpha alpha7 Nicotinic Acetylcholine Receptor Mecamylamine Nicotine Carrageenan Acetylcholine
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Saeed Rubina W
Laboratory of Medicinal Biochemistry, Institute for Medical Research at North Shore-LIJ, Manhasset, NY 11030, USA.
Varma Santosh
Peng-Nemeroff Tina
Sherry Barbara
Balakhaneh David
Huston Jared
Tracey Kevin J
Al-Abed Yousef
Metz Christine N
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20040463
Published
2005-04-04
Pages
1113-23
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2213139
Subset
IM
Grants
NCRR NIH HHS · M01 RR018535 · United States
External Links
PubMed source DOI: 10.1084/jem.20040463 PMC Full Text View journal details
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