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

ABSTRACT: While interleukin-1? (IL-1?) is a potent pro-inflammatory cytokine essential for host defense, high systemic levels cause life-threatening inflammatory syndromes. ATP, a stimulus of IL-1? maturation, is released from damaged cells along with ?-nicotinamide adenine dinucleotide (?-NAD). Here, we tested the hypothesis that ?-NAD controls ATP-signaling and, hence, IL-1? 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 ?-NAD. IL-1? was measured in cell culture supernatants. The roles of P2Y receptors, nicotinic acetylcholine receptors (nAChRs), and Ca²⁺-independent phospholipase A2 (iPLA2?, PLA2G6) were investigated using specific inhibitors and gene-silencing. Exogenous ?-NAD signaled via P2Y receptors and dose-dependently (IC₅₀ = 15 µM) suppressed the BzATP-induced IL-1? release. Signaling involved iPLA2?, release of a soluble mediator, and nAChR subunit ?9. Patch-clamp experiments revealed that ?-NAD inhibited BzATP-induced ion currents. In conclusion, we describe a novel triple membrane-passing signaling cascade triggered by extracellular ?-NAD that suppresses ATP-induced release of IL-1? 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.

SUBMITTER: Hiller SD 

PROVIDER: S-EPMC5979475 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature