Auto/paracrine control of inflammatory cytokines by acetylcholine in macrophage-like U937 cells through nicotinic receptors
Auto/paracrine control of inflammatory cytokines by acetylcholine in macrophage-like U937 cells through nicotinic receptors
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DOI：
10.1016/j.intimp.2009.12.001
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发表时间：
2010-03-01
影响因子：
5.6
通讯作者：
Grando, Sergei A.
中科院分区：
文献类型：
--
作者：
Chernyavsky, Alexander I.;Arredondo, Juan;Grando, Sergei A.
虽然乙酰胆碱（ACh）以其神经递质功能而闻名，但最近的研究表明，它还作为一种免疫细胞因子，通过“胆碱能（烟碱）抗炎途径”阻止巨噬细胞活化。在本研究中，我们利用巨噬细胞样U937细胞，通过这些细胞中表达的烟碱类乙酰胆碱受体（nAChRs），阐明了自分泌/旁分泌乙酰胆碱对细胞因子产生的生理调控机制。脂多糖刺激细胞可上调α 1、α 4、α 5、α 7、α 10、α 1和β 3亚基的表达，下调α 6和β 2亚基的表达，而α 9和β 4 mrna的相对数量未发生变化。不同的nAChR亚型对促炎性和抗炎性细胞因子的产生有不同的调节。tnf - α基因的表达抑制主要由α -班加罗毒素敏感的nAChRs介导，而IL-6和IL-18基因的表达抑制主要由甲胺敏感的nAChRs介导。Mec-和α - btx敏感的nachr对IL-1 β基因的表达调节同样有效。自分泌/旁分泌ACh对IL-10产生的上调主要通过α - 7 nAChR介导。这些发现为烟碱激动剂如何控制炎症提供了新的见解，从而为开发基于烟碱激动剂nAChR亚型选择性的新型免疫调节疗法奠定了基础。(C) 2009 Elsevier B.V.版权所有
Although acetylcholine (ACh) is well known for its neurotransmitter function, recent studies have indicated that it also functions as an immune cytokine that prevents macrophage activation through a 'cholinergic (nicotinic) anti-inflammatory pathway'. In this study, we used the macrophage-like U937 cells to elucidate the mechanisms of the physiologic control of cytokine production by auto/paracrine ACh through the nicotinic class of ACh receptors (nAChRs) expressed in these cells. Stimulation of cells with lipopolysaccharide up-regulated expression of alpha 1, alpha 4, alpha 5, alpha 7, alpha 10, beta 1 and beta 3 subunits, down-regulated alpha 6 and beta 2 subunits, and did not alter the relative quantity of alpha 9 and beta 4 mRNAs. Distinct nAChR subtypes showed differential regulation of the production of pro- and anti-inflammatory cytokines. While inhibition of the expression of the TNF-alpha gene was mediated predominantly by the alpha-bungarotoxin sensitive nAChRs, that of the IL-6 and IL-18 genes-by the mecamylamine-sensitive nAChRs. Both the Mec- and alpha Btx-sensitive nAChRs regulated expression of the IL-1 beta gene equally efficiently. Upregulation of IL-10 production by auto/paracrine ACh was mediated predominantly through alpha 7 nAChR. These findings offer a new insight on how nicotinic agonists control inflammation, thus laying a groundwork for the development of novel immunomodulatory therapies based on the nAChR subtype selectivity of nicotinic agonists. (C) 2009 Elsevier B.V. All rights reserved.