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-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.
Rehani
Kunal
K
Oral Health and Systemic Disease Research Group, University of Louisville School of Dentistry, 501 S Preston Street, Louisville, KY 40292, USA.
Scott
David A
DA
Renaud
Diane
D
Hamza
Hashir
H
Williams
Lisa R
LR
Wang
Huizhi
H
Martin
Michael
M
D002478:Cells, Cultured; D018678:Cholinergic Agents / Q000494:pharmacology; D003367:Cotinine / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000502:physiology; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011950:Receptors, Cholinergic / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018678:Cholinergic Agents; D016328:NF-kappa B; D011950:Receptors, Cholinergic; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D003367:Cotinine