title: p47phox deficiency impairs NF-kappa B activation and host defense in Pseudomonas pneumonia.
abstract: 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.
authors.affiliation: Department of Veterans Affairs and Division of Allergy, Pulmonary and Critical Care, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. ruxana.sadikot@Vanderbilt.edu
authors.forename: Ruxana T
authors.initials: RT
authors.lastname: Sadikot
authors.forename: Heng
authors.initials: H
authors.lastname: Zeng
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Yull
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Dong-sheng
authors.initials: DS
authors.lastname: Cheng
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Kernodle
authors.forename: E Duco
authors.initials: ED
authors.lastname: Jansen
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Contag
authors.forename: Brahm H
authors.initials: BH
authors.lastname: Segal
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: John W
authors.initials: JW
authors.lastname: Christman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D007113:Immunity, Innate / Q000235:genetics; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D011552:Pseudomonas Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D011956:Receptors, Cell Surface / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors
chemical_list: D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1