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?-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

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Publications

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

Hiller Sebastian Daniel SD Heldmann Sarah S Richter Katrin K Jurastow Innokentij I Küllmar Mira M Hecker Andreas A Wilker Sigrid S Fuchs-Moll Gabriele G Manzini Ivan I Schmalzing Günther G Kummer Wolfgang W Padberg Winfried W McIntosh J Michael JM Damm Jelena J Zakrzewicz Anna A Grau Veronika V

International journal of molecular sciences 20180410 4

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')-<i>O< ...[more]

PMID: 29642561

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Project description:One of the biochemical abnormalities found in diabetic tissues is a decrease in the cytosolic oxidized to reduced forms of the nicotinamide adenine dinucleotide ratio (NAD+ /NADH also known as pseudohypoxia) caused by oxidation of excessive substrates (glucose through the polyol pathway, free fatty acids and lactate). Subsequently, a decline in NAD+ levels as a result of the activation of poly adenine nucleotide diphosphate-ribose polymerase (mainly in type 1 diabetes) or the inhibition of adenine nucleotide monophosphate-activated protein kinase (in type 2 diabetes). Thus, replenishment of NAD+ levels by nicotinamide-related compounds could be beneficial. However, these compounds also increase nicotinamide catabolites that cause oxidative stress. This is particularly troublesome for patients with diabetes, because they have impaired nicotinamide salvage pathway reactions at the level of nicotinamide phosphoribosyl transferase and phosphoribosyl pyrophosphate, which occurs by the following mechanisms. First, phosphoribosyl pyrophosphate synthesis from pentose phosphate pathway is compromised by a decrease in plasma thiamine and transketolase activity. Second, nicotinamide phosphoribosyl transferase expression is decreased because of reduced adenosine monophosphate-activated protein kinase activity, which occurs in type 2 diabetes. The adenosine monophosphate-activated protein kinase inhibition is caused by an activation of protein kinase C and D1 as a result of enhanced diacylglycerol synthesis caused by pseudohypoxia and increased fatty acids levels. In this regard, nicotinamide-related compounds should be given with caution to treat diabetes. To minimize the risk and maximize the benefit, nicotinamide-related compounds should be taken with insulin sensitizers (for type 2 diabetes), polyphenols, benfotiamine, acetyl-L-carnitine and aldose reductase inhibitors. The efficacy of these regimens can be monitored by measuring serum NAD+ and urinary nicotinamide catabolites.

Dataset Information

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

Publications

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

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