title: Phosphocholine-Modified Macromolecules and Canonical Nicotinic Agonists Inhibit ATP-Induced IL-1β Release.
abstract: IL-1β is a potent proinflammatory cytokine of the innate immune system that is involved in host defense against infection. However, increased production of IL-1β plays a pathogenic role in various inflammatory diseases, such as rheumatoid arthritis, gout, sepsis, stroke, and transplant rejection. To prevent detrimental collateral damage, IL-1β release is tightly controlled and typically requires two consecutive danger signals. LPS from Gram-negative bacteria is a prototypical first signal inducing pro-IL-1β synthesis, whereas extracellular ATP is a typical second signal sensed by the ATP receptor P2X7 that triggers activation of the NLRP3-containing inflammasome, proteolytic cleavage of pro-IL-1β by caspase-1, and release of mature IL-1β. Mechanisms controlling IL-1β release, even in the presence of both danger signals, are needed to protect from collateral damage and are of therapeutic interest. In this article, we show that acetylcholine, choline, phosphocholine, phosphocholine-modified LPS from Haemophilus influenzae, and phosphocholine-modified protein efficiently inhibit ATP-mediated IL-1β release in human and rat monocytes via nicotinic acetylcholine receptors containing subunits α7, α9, and/or α10. Of note, we identify receptors for phosphocholine-modified macromolecules that are synthesized by microbes and eukaryotic parasites and are well-known modulators of the immune system. Our data suggest that an endogenous anti-inflammatory cholinergic control mechanism effectively controls ATP-mediated release of IL-1β and that the same mechanism is used by symbionts and misused by parasites to evade innate immune responses of the host.
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, D-35385 Giessen, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Hecker
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, D-35385 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, D-35385 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, D-35385 Giessen, Germany; Institute of Animal Physiology, Justus-Liebig-University Giessen, D-35392 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, D-35385 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, D-35385 Giessen, Germany;
authors.forename: Srebrena
authors.initials: S
authors.lastname: Atanasova
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, D-35385 Giessen, Germany;
authors.forename: Verena
authors.initials: V
authors.lastname: Mathes
authors.affiliation: Protein Analytics, Institute of Biochemistry, Justus-Liebig-University Giessen, D-35392 Giessen, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Timm
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, D-35385 Giessen, Germany;
authors.forename: Sabrina
authors.initials: S
authors.lastname: Lerner
authors.affiliation: Department of Pharmacology, Goethe University College of Pharmacy, D-60438 Frankfurt, Germany;
authors.forename: Jochen
authors.initials: J
authors.lastname: Klein
authors.affiliation: Institute for Immunology, Philipps-University Marburg, D-35043 Marburg, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Kaufmann
authors.affiliation: Institute for Immunology, Philipps-University Marburg, D-35043 Marburg, Germany;
authors.forename: Stefan
authors.initials: S
authors.lastname: Bauer
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, D-35385 Giessen, Germany;
authors.forename: Winfried
authors.initials: W
authors.lastname: Padberg
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University Giessen, D-35392 Giessen, Germany;
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kummer
authors.affiliation: Department of Respiratory Medicine, Hannover Medical School, D-30625 Hannover, Germany;
authors.forename: Sabina
authors.initials: S
authors.lastname: Janciauskiene
authors.affiliation: Institute of Animal Physiology, Justus-Liebig-University Giessen, D-35392 Giessen, Germany; Department of Physiology, University of Otago, Dunedin 9054, New Zealand; and.
authors.forename: Martin
authors.initials: M
authors.lastname: Fronius
authors.affiliation: Division of Chemistry, Department of Physics, Chemistry and Biology, Linköping University, S-58183 Linköping, Sweden.
authors.forename: Elke K H
authors.initials: EK
authors.lastname: Schweda
authors.affiliation: Protein Analytics, Institute of Biochemistry, Justus-Liebig-University Giessen, D-35392 Giessen, Germany;
authors.forename: Günter
authors.initials: G
authors.lastname: Lochnit
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, D-35385 Giessen, Germany; Veronika.Grau@chiru.med.uni-giessen.de.
authors.forename: Veronika
authors.initials: V
authors.lastname: Grau
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002794:Choline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000737:chemistry / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010767:Phosphorylcholine / Q000737:chemistry; D034622:RNA Interference; D051381:Rats; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020298:U937 Cells; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: C493739:CHRNA10 protein, human; C498540:CHRNA9 protein, human; C579167:Chrna7 protein, human; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D010767:Phosphorylcholine; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D009538:Nicotine; D000255:Adenosine Triphosphate; D002794:Choline; D000109:Acetylcholine