Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation.
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.
Saeed
Rubina W
RW
Laboratory of Medicinal Biochemistry, Institute for Medical Research at North Shore-LIJ, Manhasset, NY 11030, USA.
Varma
Santosh
S
Peng-Nemeroff
Tina
T
Sherry
Barbara
B
Balakhaneh
David
D
Huston
Jared
J
Tracey
Kevin J
KJ
Al-Abed
Yousef
Y
Metz
Christine N
CN
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002351:Carrageenan; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002464:Cell Migration Inhibition; D018678:Cholinergic Agents / Q000494:pharmacology*; D017931:DNA Primers; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology*; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists; D010586:Phagocytes / Q000276:immunology / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012790:Shwartzman Phenomenon / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014630:Vagus Nerve / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
D015815:Cell Adhesion Molecules; D018678:Cholinergic Agents; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D017931:DNA Primers; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; D008464:Mecamylamine; D009538:Nicotine; D002351:Carrageenan; D000109:Acetylcholine