Regulation of phagocyte NADPH oxidase by hydrogen peroxide through a Ca2+/c-Abl signaling pathway

Amina El Jamali, Anthony J. Valente, Robert A. Clark

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

The importance of H2O2 as a cellular signaling molecule has been demonstrated in a number of cell types and pathways. Here we explore a positive feedback mechanism of H2O2-mediated regulation of the phagocyte respiratory burst NADPH oxidase (NOX2). H2O2 induced a dose-dependent stimulation of superoxide production in human neutrophils, as well as in K562 leukemia cells overexpressing NOX2 system components. Stimulation was abrogated by the addition of catalase, the extracellular Ca2+ chelator BAPTA, the T-type Ca2+ channel inhibitor mibefradil, the PKCδ inhibitor rottlerin, or the c-Abl nonreceptor tyrosine kinase inhibitor imatinib mesylate or by overexpression of a dominant-negative form of c-Abl. H2O2 induced phosphorylation of tyrosine 311 on PKCδ and this activating phosphorylation was blocked by treatment with rottlerin, imatinib mesylate, or BAPTA. Rac GTPase activation in response to H2O2 was abrogated by BAPTA, imatinib mesylate, or rottlerin. In conclusion, H2O2 stimulates NOX2-mediated superoxide generation in neutrophils and K562/NOX2 cells via a signaling pathway involving Ca2+ influx and c-Abl tyrosine kinase acting upstream of PKCδ. This positive feedback regulatory pathway has important implications for amplifying the innate immune response and contributing to oxidative stress in inflammatory disorders.

Original languageEnglish (US)
Pages (from-to)798-810
Number of pages13
JournalFree Radical Biology and Medicine
Volume48
Issue number6
DOIs
StatePublished - Mar 15 2010

Keywords

  • Free radicals
  • Hydrogen peroxide
  • NADPH oxidase
  • NOX2
  • Neutrophil
  • Signaling
  • Superoxide
  • c-Abl, Calcium

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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