Pneumologie 2015; 69 - A37
DOI: 10.1055/s-0035-1556629

β-NAD inhibits ATP-mediated interleukin-1β release

S Hiller 1, A Zakrzewicz 1, S Wilker 1, I Jurastow 2, A Hecker 1, W Kummer 2, 3, W Padberg 1, V Grau 1, 3
  • 1Laboratory of Experimental Surgery, Gießen
  • 2Institute of Anatomy and Cell Biology, Gießen
  • 3Members of the German Centre for Lung Research

Introduction:

Interleukin-1β (IL-1β) is a potent pro-inflammatory cytokine, which plays a central role in host defense. High systemic IL-1β levels, however, can result in life-threatening systemic inflammation and acute lung injury. Release of IL-1β is typically controlled by two consecutive danger signals. Lipopolysaccharide (LPS) can be the first signal inducing the synthesis of pro-IL-1β. Extracellular ATP is a prototypical second danger signal, which leads to inflammasome activation, cleavage of pro-IL-1β and release of mature IL-1β. β-Nicotinamide adenine dinucleotide (β-NAD) is a co-enzyme for redox reactions, functions as a neurotransmitter and seems to modulate immune reactions. We test the hypothesis that β-NAD regulates ATP-induced release of IL-1β from LPS-primed monocytes.

Materials:

U937 cells, a human monocytic cell line, were primed with LPS for 5 hours followed by stimulation with BzATP, a specific ligand for the ATP receptor P2X7, in the presence or absence of β-NAD. Release of IL-1β into the cell culture supernatant was measured by ELISA, 30 minutes later. Receptors for β-NAD were targeted by specific inhibitors (P2Y1: MRS2279; P2Y11: NF340) and siRNA technology. In addition, antagonists of nicotinic acetylcholine receptors (nAChR) were used.

Results:

BzATP induced release of IL-1β by U937 cells was dose-dependently suppressed by addition of β-NAD. The suppressive effect of β-NAD was predominantly mediated via receptor P2Y11 and was sensitive to antagonists of nAChR subunits containing α7, α9 and/or α10.

Discussion:

We describe a novel anti-inflammatory mechanism triggered by extracellular β-NAD, which efficiently suppresses ATP-induced release of IL-1β from human monocytic cells. This effect is mediated by receptor P2Y11, which activates nAChR by a yet unknown mechanism and inhibits ATP-induced IL-1β release from human monocytes. Considering the high clinical relevance of IL-1β, our data may lead to new therapies controlling severe inflammation.

*Presenting author