Auto/paracrine control of inflammatory cytokines by acetylcholine in macrophage-like U937 cells through nicotinic receptors

作者：Chernyavsky Alexander I; Arredondo Juan; Skok Maryna; Grando Sergei A^*

来源：International Immunopharmacology, 2010, 10(3): 308-315.

DOI：10.1016/j.intimp.2009.12.001

• Nicotinic acetylcholine receptors
• TNF-alpha
• IL-1 beta
• IL-6
• IL-10
• IL-18

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.

• 出版日期2010-3