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The Journal of Immunology, 2003, 170: 6257-6265.
Copyright © 2003 by The American Association of Immunologists

A Prominent Role for Airway Epithelial NF-{kappa}B Activation in Lipopolysaccharide-Induced Airway Inflammation1

Matthew E. Poynter2,*, Charles G. Irvin* and Yvonne M. W. Janssen-Heininger{dagger}

Vermont Lung Center and Departments of * Medicine and {dagger} Pathology, University of Vermont, Burlington, VT 05405

To reveal the causal role of airway epithelial NF-{kappa}B activation in evoking airway inflammation, a transgenic mouse was created expressing a mutant version of the inhibitory protein I-{kappa}B{alpha}. This I-{kappa}B{alpha} superrepressor (I-{kappa}B{alpha}SR) acts to repress NF-{kappa}B activation exclusively in airway epithelial cells, under the transcriptional control of the rat CC10 promoter (CC10-I-{kappa}B{alpha}SR). Compared with transgene-negative littermates, intranasal instillation of LPS did not induce nuclear translocation of NF-{kappa}B in airway epithelium of CC10-I-{kappa}B{alpha}SR transgenic mice. Consequently, the influx of neutrophils into the airways and secretion of the NF-{kappa}B-regulated neutrophilic chemokine, macrophage-inflammatory protein-2, and the inflammatory cytokine, TNF-{alpha}, were markedly reduced in CC10-I-{kappa}B{alpha}SR mice relative to the transgene-negative mice exposed to LPS. Despite an inability to activate NF-{kappa}B in airway epithelium, resident alveolar macrophages from transgene-positive mice were capable of activating NF-{kappa}B 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-{kappa}B signaling in these cells is important for modulating innate immune responses to microbial products.




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