A key role for redox signaling in rapid P2X7 receptor-induced IL-1 beta processing in human monocytes.
J Immunol
; 180(12): 8410-20, 2008 Jun 15.
Article
in En
| MEDLINE
| ID: mdl-18523309
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Monocytes
/
Signal Transduction
/
Protein Processing, Post-Translational
/
Receptors, Purinergic P2
/
Interleukin-1beta
Limits:
Humans
Language:
En
Journal:
J Immunol
Year:
2008
Document type:
Article
Affiliation country: