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

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-κB system (TNF-α, IL-1β, 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 α7 nAChR; and is PI3K/GSK-3β-dependent; but NF-κB-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.