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Int. J. Mol. Sci. 2018, 19(4), 1126; https://doi.org/10.3390/ijms19041126

β-Nicotinamide Adenine Dinucleotide (β-NAD) Inhibits ATP-Dependent IL-1β Release from Human Monocytic Cells

1
Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, German Centre for Lung Research (DZL), Feulgen-Str. 10-12, D-35385 Giessen, Germany
2
Institute of Anatomy and Cell Biology, Justus-Liebig-University Giessen, German Centre for Lung Research (DZL), Aulweg 123, D-35385 Giessen, Germany
3
Department of Animal Physiology and Molecular Biomedicine, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 38, D-35392 Giessen, Germany
4
Institute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, D-52072 Aachen, Germany
5
Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA
6
George E. Wahlen Veterans Affairs Medical Center, 500 Foothill Drive, Salt Lake City, Salt Lake City, UT 84148, USA
7
Department of Psychiatry, University of Utah, 501 Chipeta Way, Salt Lake City, UT 84108, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 27 February 2018 / Revised: 29 March 2018 / Accepted: 5 April 2018 / Published: 10 April 2018
(This article belongs to the Special Issue Purinergic Signalling in Cancer and Inflammation)
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Abstract

While interleukin-1β (IL-1β) is a potent pro-inflammatory cytokine essential for host defense, high systemic levels cause life-threatening inflammatory syndromes. ATP, a stimulus of IL-1β maturation, is released from damaged cells along with β-nicotinamide adenine dinucleotide (β-NAD). Here, we tested the hypothesis that β-NAD controls ATP-signaling and, hence, IL-1β release. Lipopolysaccharide-primed monocytic U937 cells and primary human mononuclear leukocytes were stimulated with 2′(3′)-O-(4-benzoyl-benzoyl)ATP trieethylammonium salt (BzATP), a P2X7 receptor agonist, in the presence or absence of β-NAD. IL-1β was measured in cell culture supernatants. The roles of P2Y receptors, nicotinic acetylcholine receptors (nAChRs), and Ca2+-independent phospholipase A2 (iPLA2β, PLA2G6) were investigated using specific inhibitors and gene-silencing. Exogenous β-NAD signaled via P2Y receptors and dose-dependently (IC50 = 15 µM) suppressed the BzATP-induced IL-1β release. Signaling involved iPLA2β, release of a soluble mediator, and nAChR subunit α9. Patch-clamp experiments revealed that β-NAD inhibited BzATP-induced ion currents. In conclusion, we describe a novel triple membrane-passing signaling cascade triggered by extracellular β-NAD that suppresses ATP-induced release of IL-1β by monocytic cells. This cascade links activation of P2Y receptors to non-canonical metabotropic functions of nAChRs that inhibit P2X7 receptor function. The biomedical relevance of this mechanism might be the control of trauma-associated systemic inflammation. View Full-Text
Keywords: β-NAD; β-nicotinamide adenine dinucleotide; CHRNA7; CHRNA9; CHRNA10; inflammasome; interleukin-1β; iPLA2β; monocyte; P2RY1; P2RY11; PLA2G6; U937 cells β-NAD; β-nicotinamide adenine dinucleotide; CHRNA7; CHRNA9; CHRNA10; inflammasome; interleukin-1β; iPLA2β; monocyte; P2RY1; P2RY11; PLA2G6; U937 cells
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Hiller, S.D.; Heldmann, S.; Richter, K.; Jurastow, I.; Küllmar, M.; Hecker, A.; Wilker, S.; Fuchs-Moll, G.; Manzini, I.; Schmalzing, G.; Kummer, W.; Padberg, W.; McIntosh, J.M.; Damm, J.; Zakrzewicz, A.; Grau, V. β-Nicotinamide Adenine Dinucleotide (β-NAD) Inhibits ATP-Dependent IL-1β Release from Human Monocytic Cells. Int. J. Mol. Sci. 2018, 19, 1126.

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