Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Administration, Inhalation
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Animals
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Crosses, Genetic
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Cytokines / antagonists & inhibitors
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Cytokines / biosynthesis
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Gene Expression Regulation / immunology
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Humans
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I-kappa B Kinase
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I-kappa B Proteins / genetics
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / prevention & control
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Lipopolysaccharides / toxicity*
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Lung / immunology
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Lung / metabolism
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Lung / pathology
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Macrophages, Alveolar / immunology
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Macrophages, Alveolar / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Transgenic
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NF-KappaB Inhibitor alpha
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / metabolism
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NF-kappa B / physiology*
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Protein Serine-Threonine Kinases / genetics
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Proteins / genetics
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Rats
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Respiratory Mucosa / enzymology
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Respiratory Mucosa / immunology
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Respiratory Mucosa / metabolism*
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Respiratory Mucosa / pathology*
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Transcriptional Activation / genetics
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Transcriptional Activation / immunology
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Transgenes
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Uteroglobin*
Substances
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Cytokines
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I-kappa B Proteins
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Lipopolysaccharides
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NF-kappa B
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NFKBIA protein, human
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Nfkbia protein, mouse
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Nfkbia protein, rat
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Proteins
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SCGB1A1 protein, human
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Scgb1a1 protein, mouse
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Scgb1a1 protein, rat
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NF-KappaB Inhibitor alpha
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Uteroglobin
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Protein Serine-Threonine Kinases
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse