A prominent role for airway epithelial NF-kappa B activation in lipopolysaccharide-induced airway inflammation.
To reveal the causal role of airway epithelial NF-kappaB activation in evoking airway inflammation, a transgenic mouse was created expressing a mutant version of the inhibitory protein I-kappaBalpha. This I-kappaBalpha superrepressor (I-kappaBalpha(SR)) acts to repress NF-kappaB activation exclusively in airway epithelial cells, under the transcriptional control of the rat CC10 promoter (CC10-I-kappaBalpha(SR)). Compared with transgene-negative littermates, intranasal instillation of LPS did not induce nuclear translocation of NF-kappaB in airway epithelium of CC10-I-kappaBalpha(SR) transgenic mice. Consequently, the influx of neutrophils into the airways and secretion of the NF-kappaB-regulated neutrophilic chemokine, macrophage-inflammatory protein-2, and the inflammatory cytokine, TNF-alpha, were markedly reduced in CC10-I-kappaBalpha(SR) mice relative to the transgene-negative mice exposed to LPS. Despite an inability to activate NF-kappaB in airway epithelium, resident alveolar macrophages from transgene-positive mice were capable of activating NF-kappaB in a manner indistinguishable from transgene-negative mice. These findings demonstrate that airway epithelial cells play a prominent role in orchestrating the airway inflammatory response to LPS and suggest that NF-kappaB signaling in these cells is important for modulating innate immune responses to microbial products.
Poynter
Matthew E
ME
Vermont Lung Center and Department of Medicine, University of Vermont, Burlington, VT 05405, USA. matthew.poynter@uvm.edu
Irvin
Charles G
CG
Janssen-Heininger
Yvonne M W
YM
D000280:Administration, Inhalation; D000818:Animals; D003433:Crosses, Genetic; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011506:Proteins / Q000235:genetics; D051381:Rats; D020545:Respiratory Mucosa / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology; D019076:Transgenes; D014598:Uteroglobin
D016207:Cytokines; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D011506:Proteins; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; C556391:Scgb1a1 protein, rat; D000072000:NF-KappaB Inhibitor alpha; D014598:Uteroglobin; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse