A key role for redox signaling in rapid P2X7 receptor-induced IL-1 beta processing in human monocytes

James Hewinson, Samantha F Moore, Christian Glover, Andrew G Watts, Amanda B MacKenzie

Research output: Contribution to journalArticle (Academic Journal)peer-review

88 Citations (Scopus)

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 languageEnglish
Pages (from-to)8410-20
Number of pages11
JournalJournal of Immunology
Volume180
Issue number12
Publication statusPublished - 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

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