Enhanced inflammatory responses of chronic granulomatous disease leukocytes involve ROS-independent activation of NF-κB

Johan Bylund, Kelly L. MacDonald, Kelly L. Brown, Piotr Mydel, L. Vincent Collins, Robert E.W. Hancock, David P. Speert

Research output: Contribution to journalArticlepeer-review

79 Citations (Scopus)

Abstract

Reactive oxygen species (ROS) generated by the cellular NADPH-oxidase are crucial for phagocytic killing of ingested microbes and have been implicated as signaling molecules in various processes. For example, ROS are thought to be involved in activation of the transcription factor NF-κB, central for mediating production of proinflammatory cytokines in response to inflammatory stimuli. Several studies have demonstrated that inhibitors of the NADPH-oxidase interfere with NF-κB activation and production of proinflammatory cytokines. Curiously, patients with chronic granulomatous disease (CGD), an immunodeficiency characterized by an inability to produce ROS, are not only predisposed to severe infections, but also frequently develop various inflammatory complications indicative of exaggerated inflammatory responses. Here, we show that human CGD leukocytes display a hyperinflammatory phenotype with increased production of proinflammatory cytokines in response to stimulation with Toll-like receptor agonists. The hyperinflammatory phenotype was also evident in mononuclear cells from CGD mice (gp91phox-/-), but not in control cells in the presence of NADPH-oxidase inhibitor diphenyleneiodonium, probably reflecting NADPH-oxidase-independent effects of the inhibitor. Furthermore, we show that the major steps involved in NF-κB activation were intact in human CGD cells. These data indicate that ROS were nonessential for activation of NF-κB and their production may even attenuate inflammation.

Original languageEnglish
Pages (from-to)1087-1096
Number of pages10
JournalEuropean Journal of Immunology
Volume37
Issue number4
DOIs
Publication statusPublished or Issued - 1 Apr 2007
Externally publishedYes

Keywords

  • Immunodeficiencies
  • Inflammation
  • NF-κB pathway

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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