Surfactant inhibits ATP-induced release of interleukin-1 via nicotinic acetylcholine receptors

Abstract

Interleukin (IL)-1Β is a potent pro-inflammatory cytokine of innate immunity involved in host defense. High systemic IL-1Β levels, however, cause life-threatening inflammatory diseases, including systemic inflammatory response syndrome. In response to various danger signals, the proform of IL-1Β is synthesized and stays in the cytoplasm unless a second signal, such as extracellular ATP, activates the inflammasome, which enables processing and release of mature IL-1Β. As pulmonary surfactant is known for its antiinflammatory properties, we hypothesize that surfactant inhibitsATP-induced release of IL-1Β. Lipopolysaccharide-primed monocytic U937 cells were stimulated with an ATP analog in the presence of natural or synthetic surfactant composed of recombinant surfactant protein (rSP)-C, palmitoylphosphatidylglycerol, and dipalmitoylphosphatidylcholine (DPPC). Both surfactant preparations dose-dependently inhibited IL-1Β release from U937 cells. DPPC was the active constituent of surfactant, whereas rSP-C and palmitoylphosphatidylglycerol were inactive. DPPC was also effective in primary mononuclear leukocytes isolated from human blood. Experiments with nicotinic antagonists, siRNA technology, and patchclamp experiments suggested that stimulation of nicotinic acetylcholine receptors (nAChRs) containing subunit ?9 results in a complete inhibition of the ion channel function of ATP receptor, P2X7. In conclusion, the surfactant constituent, DPPC, efficiently inhibits ATP-induced inflammasome activation and maturation of IL-1Β in human monocytes by a mechanism involving nAChRs.—Backhaus, S., A. Zakrzewicz, K. Richter, J. Damm, S. Wilker, G. Fuchs-Moll, M. Küllmar, A. Hecker, I. Manzini, C. Ruppert, J. M. McIntosh, W. Padberg, and V. Grau. Surfactant inhibits ATP-induced release of interleukin-1Β via nicotinic acetylcholine receptors.