TY - JOUR
T1 - A key role for redox signaling in rapid P2X7 receptor-induced IL-1 β processing in human monocytes
AU - Hewinson, J
AU - Moore, S F
AU - Glover, C
AU - Watts, Andrew
AU - Mackenzie, Amanda B
PY - 2008/6/15
Y1 - 2008/6/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=50249090764&partnerID=8YFLogxK
UR - http://www.jimmunol.org/cgi/content/abstract/180/12/8410
M3 - Article
SN - 0022-1767
VL - 180
SP - 8410
EP - 8420
JO - The Journal of Immunology
JF - The Journal of Immunology
IS - 12
ER -