p47phox Deficiency Impairs NF-κB Activation and Host Defense in Pseudomonas Pneumonia

Ruxana T. Sadikot, Heng Zeng, Fiona E. Yu, Bo Li, Dong Sheng Cheng, Douglas S. Kernodle, E. Duco Jansen, Christopher H. Contag, Brahm H. Segal, Steven M. Holland, Timothy S. Blackwell, John W. Christman

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

We examined the role of redox signaling generated by NADPH oxidase in activation of NF-κB and host defense against Pseudomonas aeruginosa pneumonia. Using mice with an NF-κB-driven luciferase reporter construct (HIV-LTR/luciferase (HLL)), we found that intratracheal administration of P. aeruginosa resulted in a dose-dependent neutrophilic influx and activation of NF-κB. To determine the effects of reactive oxygen species generated by the NADPH oxidase system on activation of NF-κB, we crossbred mice deficient in p47phox with NF-κB reporter mice (p47 phox-/-HLL). These p47phox-/-HLL mice were unable to activate NF-κB to the same degree as HLL mice with intact NADPH oxidase following P. aeruginosa infection. In addition, lung TNF-α levels were significantly lower in p47phox-/-HLL mice compared with HLL mice. Bacterial clearance was impaired in p47phox-/-HLL mice. In vitro studies using bone marrow-derived macrophages showed that Toll-like receptor 4 was necessary for NF-κB activation following treatment with P. aeruginosa. Additional studies with macrophages from p47phox-/- mice confirmed that redox signaling was necessary for maximal Toll-like receptor 4-dependent NF-κB activation in this model. These data indicate that the NADPH oxidase-dependent respiratory burst stimulated by Pseudomonas infection contributes to host defense by modulating redox-dependent signaling through the NF-κB pathway.

Original languageEnglish (US)
Pages (from-to)1801-1808
Number of pages8
JournalJournal of Immunology
Volume172
Issue number3
DOIs
StatePublished - Feb 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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