A key role for redox signaling in rapid P2X7 receptor-induced IL-1 beta processing in human monocytes
| Autor: | Andrew G. Watts, Christian Glover, Amanda B. Mackenzie, Samantha F Moore, James Hewinson |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Immunology
Interleukin-1beta Stimulation Nitric Oxide Monocytes chemistry.chemical_compound Adenosine Triphosphate Cell Line Tumor Immunology and Allergy Humans Receptor chemistry.chemical_classification Reactive oxygen species NADPH oxidase S-Nitrosothiols biology Chemistry Superoxide Receptors Purinergic P2 Purinergic receptor Caspase 1 NADPH Oxidases Extracellular Fluid Oxidants Cell biology Enzyme Activation biology.protein Receptors Purinergic P2X7 Signal transduction Ion Channel Gating Oxidation-Reduction Protein Processing Post-Translational Peroxynitrite Signal Transduction |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 180(12) |
| ISSN: | 0022-1767 |
| Popis: | P2X7 receptors (P2X7Rs) are ATP-gated ion channels that trigger caspase-1 activation in the presence of TLR ligands. Inflammatory caspase-1 is responsible for the proteolytic activation of IL-1β. However, the signaling events that couple P2X7Rs to caspase-1 activation remain undefined. In this study we demonstrate that ATP-induced cellular oxidation is critical for caspase-1 activation and subsequent IL-1β processing. Purinergic receptor stimulation, including P2X7Rs, of endotoxin-primed human monocytes augments NADPH oxidase activity whereas concurrent purinergic receptor stimulation triggers protein denitroyslation, leading to the formation of peroxynitrite. IL-1β cleavage is blocked under conditions where superoxide anion formation is blocked or monocytes are treated with antioxidants or a peroxynitrite scavenger. Nigericin, a K+/H+ antiporter, also increases NADPH oxidase activity, leading to IL-1β and caspase-1 processing that is blocked by a peroxynitrite scavenger or inhibition of NADPH oxidase. These data demonstrate that signaling via NADPH oxidase activity is fundamental for the processing of mature IL-1β induced by P2X7R stimulation. |
| Databáze: | OpenAIRE |
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