Auto/paracrine control of inflammatory cytokines by acetylcholine in macrophage-like U937 cells through nicotinic receptors.
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.
Chernyavsky
Alexander I
AI
Institute for Immunology, University of California, Irvine, CA 92697, USA.
Arredondo
Juan
J
Skok
Maryna
M
Grando
Sergei A
SA
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
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