title: Surfactant inhibits ATP-induced release of interleukin-1β via nicotinic acetylcholine receptors.
abstract: 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 known for its anti-inflammatory properties, we hypothesize that surfactant inhibits ATP-induced release of IL-1β. 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-1β 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 α9 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-1β in human monocytes by a mechanism involving nAChRs.
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Backhaus
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Zakrzewicz
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Richter
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Damm
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Wilker
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fuchs-Moll
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Mira
authors.initials: M
authors.lastname: Küllmar
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hecker
authors.affiliation: Department of Animal Physiology and Molecular Biomedicine, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Ivan
authors.initials: I
authors.lastname: Manzini
authors.affiliation: Medical Clinic II, Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Ruppert
authors.affiliation: Departments of Biology and Psychiatry, University of Utah and George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT.
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Padberg
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery Justus-Liebig-University Giessen, Giessen, Germany Veronika.Grau@chiru.med.uni-giessen.de.
authors.forename: Veronika
authors.initials: V
authors.lastname: Grau
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000494:pharmacology*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D053583:Interleukin-1beta; D021122:Protein Subunits; D011663:Pulmonary Surfactants; D011978:Receptors, Nicotinic; D015060:1,2-Dipalmitoylphosphatidylcholine; D000255:Adenosine Triphosphate
keywords: CHRNA10; CHRNA7; CHRNA9; dipalmitoylphosphatidylcholine; inflammasome; monocyte; phosphatidylcholine; purinergic receptor P2X 7