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Biochim Biophys Acta. 2008 Mar;1783(3):375-82. doi: 10.1016/j.bbamcr.2007.12.003. Epub 2007 Dec 15.

Cotinine-induced convergence of the cholinergic and PI3 kinase-dependent anti-inflammatory pathways in innate immune cells.

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1
Oral Health and Systemic Disease Research Group, University of Louisville School of Dentistry, 501 S Preston Street, Louisville, KY 40292, USA.

Abstract

Nicotine [(S)-3-(1-methyl-2-pyrrolidinyl)pyridine] is a major component of tobacco and a highly efficient acetylcholine receptor (nAChR) agonist that triggers the cholinergic anti-inflammatory pathway. We demonstrate that pre-treatment of monocytes with the stable nicotine catabolite, cotinine [(S)-1-methyl-5-(3-pyridinyl)-2-pyrrolidinone], dramatically alters the nature of the inflammatory response to Gram negative bacteria by abrogating the production of cytokines that are under the transcriptional control of the NF-kappaB system (TNF-alpha, IL-1beta, IL-6, IL-12/IL-23 p40) and shifting the response towards an IL-10-dominated anti-inflammatory profile. This anti-inflammatory phenomenon is initiated specifically by engagement of the monocytic alpha7 nAChR; and is PI3K/GSK-3beta-dependent; but NF-kappaB-independent. These mechanistic insights suggest an ability to exploit convergent, endogenous anti-inflammatory pathway(s) to either up-regulate or down-regulate the production of specific cytokine groups (pro- or anti-inflammatory cytokines) depending on the clinical necessity.

PMID:
18178163
DOI:
10.1016/j.bbamcr.2007.12.003
[Indexed for MEDLINE]
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