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Surfactant inhibits ATP-induced release of interleukin-1? via nicotinic acetylcholine receptors.

ABSTRACT: Interleukin (IL)-1? is a potent pro-inflammatory cytokine of innate immunity involved in host defense. High systemic IL-1? levels, however, cause life-threatening inflammatory diseases, including systemic inflammatory response syndrome. In response to various danger signals, the pro-form of IL-1? is synthesized and stays in the cytoplasm unless a second signal, such as extracellular ATP, activates the inflammasome, which enables processing and release of mature IL-1?. As pulmonary surfactant is known for its anti-inflammatory properties, we hypothesize that surfactant inhibits ATP-induced release of IL-1?. Lipopolysaccharide-primed monocytic U937 cells were stimulated with an ATP analog in the presence of natural or synthetic surfactant composed of recombinant surfactant protein (rSP)-C, palmitoylphosphatidylglycerol, and dipalmitoylphosphatidylcholine (DPPC). Both surfactant preparations dose-dependently inhibited IL-1? release from U937 cells. DPPC was the active constituent of surfactant, whereas rSP-C and palmitoylphosphatidylglycerol were inactive. DPPC was also effective in primary mononuclear leukocytes isolated from human blood. Experiments with nicotinic antagonists, siRNA technology, and patch-clamp experiments suggested that stimulation of nicotinic acetylcholine receptors (nAChRs) containing subunit ?9 results in a complete inhibition of the ion channel function of ATP receptor, P2X7. In conclusion, the surfactant constituent, DPPC, efficiently inhibits ATP-induced inflammasome activation and maturation of IL-1? in human monocytes by a mechanism involving nAChRs.

SUBMITTER: Backhaus S

PROVIDER: S-EPMC5454502 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Surfactant inhibits ATP-induced release of interleukin-1β via nicotinic acetylcholine receptors.

Backhaus Sören S Zakrzewicz Anna A Richter Katrin K Damm Jelena J Wilker Sigrid S Fuchs-Moll Gabriele G Küllmar Mira M Hecker Andreas A Manzini Ivan I Ruppert Clemens C McIntosh J Michael JM Padberg Winfried W Grau Veronika V

Journal of lipid research 20170412 6

Interleukin (IL)-1β is a potent pro-inflammatory cytokine of innate immunity involved in host defense. High systemic IL-1β levels, however, cause life-threatening inflammatory diseases, including systemic inflammatory response syndrome. In response to various danger signals, the pro-form of IL-1β is synthesized and stays in the cytoplasm unless a second signal, such as extracellular ATP, activates the inflammasome, which enables processing and release of mature IL-1β. As pulmonary surfactant is ...[more]

PMID: 28404637

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Project description:IntroductionCigarette smoking continues to be one of the most important behavioral causes of morbidity and mortality in the world. Varenicline, an α4β2 nicotinic acetylcholine receptor (nAChR) partial agonist, has been shown to increase smoking quit rates compared with nicotine-based products. This human laboratory, double-blind, placebo-controlled study examined varenicline and placebo effects on α4β2-nAChRs occupancy, nicotine-induced change in [11C]raclopride non-displaceable binding potential (BPND), and behavioral measures of cigarette smoking, nicotine craving, and withdrawal.MethodsCurrent nicotine dependent daily smokers (N = 17) were randomized to varenicline 1 mg twice daily or placebo for 13 days. Using positron emission tomography), we characterized α4β2-nAChRs occupancy using [18F]AZAN and dopamine receptor binding using [11C]raclopride as well as behavioral measures of cigarettes smoked, craving, and nicotine withdrawal.ResultsVarenicline compared with placebo resulted in significant reductions in [18F]AZAN BPND in multiple brain regions including thalamus, midbrain, putamen, and ventral striatum. Following administration of a controlled-dose nicotine cigarette, dopamine release was significantly suppressed in the ventral striatum in the varenicline-treated compared with the placebo group. There was a significant relationship between α4β2-nAChRs BPND measured in thalamus during the [18F]AZAN scan and nicotine-induced change in raclopride BPND in the ventral striatum.ConclusionThis is the first human study to demonstrate a direct relationship between the extent of varenicline occupancy of α4β2-nAChRs and the magnitude of dopamine release following nicotine use.ImplicationsIt has remained unclear how nicotinic receptor blockade through partial agonist medications such as varenicline promotes smoking cessation. One hypothesized mechanism is downstream dampening of the mesolimbic reward dopamine system. For the first time in human smokers, we observed a direct relationship between the extent of varenicline blockade of α4β2-nACh nicotinic receptors and the magnitude of dopamine release following smoking. This has mechanistic and therapeutic implications for improving smoking cessation interventions.

Dataset Information

Surfactant inhibits ATP-induced release of interleukin-1? via nicotinic acetylcholine receptors.

Publications

Surfactant inhibits ATP-induced release of interleukin-1β via nicotinic acetylcholine receptors.

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