A key role for redox signaling in rapid P2X(7) receptor-induced IL-1 beta processing in human monocytes

作者：Hewinson James; Moore Samantha F; Glover Christian; Watts Andrew G; MacKenzie Amanda B^*

来源：The Journal of Immunology, 2008, 180(12): 8410-8420.

DOI：10.4049/jimmunol.180.12.8410

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-1 beta. 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-1 beta 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-1 beta 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-1 beta 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-1 beta induced by P2X(7)R stimulation.

• 出版日期2008-6-15