Abstract
P2X(7) receptors (P2X(7)Rs) 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-1beta. However, the signaling events that couple P2X(7)Rs 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-1beta processing. Purinergic receptor stimulation, including P2X(7)Rs, of endotoxin-primed human monocytes augments NADPH oxidase activity whereas concurrent purinergic receptor stimulation triggers protein denitroyslation, leading to the formation of peroxynitrite. IL-1beta 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-1beta 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-1beta induced by P2X(7)R stimulation.
| Original language | English |
|---|---|
| Pages (from-to) | 8410-20 |
| Number of pages | 11 |
| Journal | Journal of Immunology |
| Volume | 180 |
| Issue number | 12 |
| Publication status | Published - 15 Jun 2008 |
Keywords
- Ion Channel Gating
- Receptors, Purinergic P2X7
- Receptors, Purinergic P2
- Enzyme Activation
- Humans
- Protein Processing, Post-Translational
- Interleukin-1beta
- Caspase 1
- Cell Line, Tumor
- S-Nitrosothiols
- Nitric Oxide
- Oxidation-Reduction
- Extracellular Fluid
- NADPH Oxidase
- Adenosine Triphosphate
- Monocytes
- Signal Transduction
- Oxidants