Cotinine-induced convergence of the cholinergic and PI3 kinase-dependent anti-inflammatory pathways in innate immune cells
Cotinine-induced convergence of the cholinergic and PI3 kinase-dependent anti-inflammatory pathways in innate immune cells
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DOI：
10.1016/j.bbamcr.2007.12.003
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发表时间：
2008-03-01
影响因子：
5.1
通讯作者：
Martin, Michael
中科院分区：
文献类型：
--
作者：
Rehani, Kunal;Scott, David A.;Martin, Michael
尼古丁[(S)-3-(1-甲基-2-吡咯烷基)吡啶]是烟草的主要成分，是一种高效的乙酰胆碱受体激动剂，可触发胆碱能抗炎途径。我们证明，用稳定的尼古丁分解代谢物Cotinine[(S)-1-methyl-5-(3-pyridinyl)-2-pyrrolidinone]，对单核细胞进行预处理，通过取消受核因子-kappa B系统转录控制的细胞因子(肿瘤坏死因子-α、IL-1β、IL-6、IL-12/IL-23p40)的产生，并将反应转向以IL-10为主的抗炎模式，从而显著改变了对革兰氏阴性细菌的炎症反应的性质。这种抗炎现象是由单核细胞α7nAChR特异性启动的，并且依赖于PI3K/GSK-3β，但不依赖于核因子-kappa B。这些机械性的见解表明，根据临床需要，有能力利用汇聚的内源性抗炎途径(S)来上调或下调特定细胞因子组(促炎或抗炎细胞因子)的产生。(C)2007爱思唯尔B.V保留所有权利。
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-kappa B system (TNF-alpha, IL-1 beta, 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 alpha 7 nAChR; and is PI3K/GSK-3 beta-dependent; but NF-kappa B-independent. These mechanistic insights suggest an ability to exploit convergent, endogenous anti-inflammatory pathway(s) to either upregulate or down-regulate the production of specific cytokine groups (pro- or anti-inflammatory cytokines) depending on the clinical necessity. (c) 2007 Elsevier B.V All rights reserved.