p47phox deficiency impairs NF-kappa B activation and host defense in Pseudomonas pneumonia.

Sadikot RT, Zeng H, Yull FE, Li B, Cheng DS, Kernodle DS, Jansen ED, Contag CH, Segal BH, Holland SM, Blackwell TS, Christman JW
J Immunol. 2004 172 (3): 1801-8

PMID: 14734763 · DOI:10.4049/jimmunol.172.3.1801

We examined the role of redox signaling generated by NADPH oxidase in activation of NF-kappaB and host defense against Pseudomonas aeruginosa pneumonia. Using mice with an NF-kappaB-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-kappaB. To determine the effects of reactive oxygen species generated by the NADPH oxidase system on activation of NF-kappaB, we crossbred mice deficient in p47(phox) with NF-kappaB reporter mice (p47(phox-/-)HLL). These p47(phox-/-)HLL mice were unable to activate NF-kappaB to the same degree as HLL mice with intact NADPH oxidase following P. aeruginosa infection. In addition, lung TNF-alpha levels were significantly lower in p47(phox-/-)HLL mice compared with HLL mice. Bacterial clearance was impaired in p47(phox-/-)HLL mice. In vitro studies using bone marrow-derived macrophages showed that Toll-like receptor 4 was necessary for NF-kappaB activation following treatment with P. aeruginosa. Additional studies with macrophages from p47(phox-/-) mice confirmed that redox signaling was necessary for maximal Toll-like receptor 4-dependent NF-kappaB 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-kappaB pathway.

MeSH Terms (21)

Animals Cells, Cultured Dose-Response Relationship, Immunologic Immunity, Innate Lung Macrophages Membrane Glycoproteins Mice Mice, Inbred C3H Mice, Inbred C57BL Mice, Inbred DBA Mice, Transgenic NADPH Oxidases Neutrophil Infiltration NF-kappa B Phosphoproteins Pneumonia, Bacterial Pseudomonas Infections Receptors, Cell Surface Signal Transduction Toll-Like Receptors

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