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Am J Respir Crit Care Med. 2008 May 1;177(9):959-69. doi: 10.1164/rccm.200707-1096OC. Epub 2008 Feb 8.

Nuclear factor-kappaB activation in airway epithelium induces inflammation and hyperresponsiveness.

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  • 1Department of Pathology, University of Vermont, Burlington, Vermont 05405, USA.

Abstract

RATIONALE:

Nuclear factor (NF)-kappaB is a prominent proinflammatory transcription factor that plays a critical role in allergic airway disease. Previous studies demonstrated that inhibition of NF-kappaB in airway epithelium causes attenuation of allergic inflammation.

OBJECTIVES:

We sought to determine if selective activation of NF-kappaB within the airway epithelium in the absence of other agonists is sufficient to cause allergic airway disease.

METHODS:

A transgenic mouse expressing a doxycycline (Dox)-inducible, constitutively active (CA) version of inhibitor of kappaB (IkappaB) kinase-beta (IKKbeta) under transcriptional control of the rat CC10 promoter, was generated.

MEASUREMENTS AND MAIN RESULTS:

After administration of Dox, expression of the CA-IKKbeta transgene induced the nuclear translocation of RelA in airway epithelium. IKKbeta-triggered activation of NF-kappaB led to an increased content of neutrophils and lymphocytes, and concomitant production of proinflammatory mediators, responses that were not observed in transgenic mice not receiving Dox, or in transgene-negative littermate control animals fed Dox. Unexpectedly, expression of the IKKbeta transgene in airway epithelium was sufficient to cause airway hyperresponsiveness and smooth muscle thickening in absence of an antigen sensitization and challenge regimen, the presence of eosinophils, or the induction of mucus metaplasia.

CONCLUSIONS:

These findings demonstrate that selective activation NF-kappaB in airway epithelium is sufficient to induce airway hyperresponsiveness and smooth muscle thickening, which are both critical features of allergic airway disease.

PMID:
18263801
PMCID:
PMC2361423
DOI:
10.1164/rccm.200707-1096OC
[PubMed - indexed for MEDLINE]
Free PMC Article
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