title: Auto/paracrine control of inflammatory cytokines by acetylcholine in macrophage-like U937 cells through nicotinic receptors.
abstract: 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.
authors.affiliation: Institute for Immunology, University of California, Irvine, CA 92697, USA.
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Chernyavsky
authors.forename: Juan
authors.initials: J
authors.lastname: Arredondo
authors.forename: Maryna
authors.initials: M
authors.lastname: Skok
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Grando
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D019898:Autocrine Communication / Q000187:drug effects*; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D007202:Indicators and Reagents; D007249:Inflammation / Q000378:metabolism*; D016753:Interleukin-10 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects*; D018722:Nicotinic Agonists / Q000494:pharmacology; D019899:Paracrine Communication / Q000187:drug effects*; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020298:U937 Cells; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; D016207:Cytokines; D007155:Immunologic Factors; D007202:Indicators and Reagents; D008070:Lipopolysaccharides; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016753:Interleukin-10; D000109:Acetylcholine