Journal article

Publication year: 2018

Journal: International Journal of Molecular Sciences

Volume number: 19

Issue number: 4

ISSN: 1422-0067

Open access status: Gold

DOI Link: https://doi.org/10.3390/ijms19041126

Publisher: MDPI

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.

Harvard Citation style: Hiller, S., Heldmann, S., Richter, K., Jurastow, I., Küllmar, M., Hecker, A., et al. (2018) β-Nicotinamide Adenine Dinucleotide (β-NAD) Inhibits ATP-Dependent IL-1β Release from Human Monocytic Cells, International Journal of Molecular Sciences, 19(4), Article e1126. https://doi.org/10.3390/ijms19041126

APA Citation style: Hiller, S., Heldmann, S., Richter, K., Jurastow, I., Küllmar, M., Hecker, A., Wilker, S., Fuchs-Moll, G., Manzini, I., Schmalzing, G., Kummer, W., Padberg, W., McIntosh, M., Damm, J., Zakrzewicz, A., & Grau, V. (2018). β-Nicotinamide Adenine Dinucleotide (β-NAD) Inhibits ATP-Dependent IL-1β Release from Human Monocytic Cells. International Journal of Molecular Sciences. 19(4), Article e1126. https://doi.org/10.3390/ijms19041126