A prominent role for airway epithelial NF-kappa B activation in lipopolysaccharide-induced airway inflammation.

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.