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 alpha1, alpha4, alpha5, alpha7, alpha10, beta1 and beta3 subunits, down-regulated alpha6 and beta2 subunits, and did not alter the relative quantity of alpha9 and beta4 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 alphaBtx-sensitive nAChRs regulated expression of the IL-1beta gene equally efficiently. Upregulation of
IL-10 production by auto/paracrine ACh was mediated predominantly through alpha7 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.