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Nuclear Factor-B Activation in Airway Epithelium Induces Inflammation and Hyperresponsiveness

¹ Department of Pathology and ² Department of Medicine, University of Vermont, Burlington, Vermont

Correspondence and requests for reprints should be addressed to Yvonne M.W. Janssen-Heininger, Ph.D., Department of Pathology, University of Vermont, Burlington, Vermont 05405. E-mail: yvonne.janssen{at}uvm.edu

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

Objectives: We sought to determine if selective activation of NF-B 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 B (IB) kinase-β (IKKβ) under transcriptional control of the rat CC10 promoter, was generated.

Measurements and Main Results: After administration of Dox, expression of the CA-IKKβ transgene induced the nuclear translocation of RelA in airway epithelium. IKKβ-triggered activation of NF-B 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 IKKβ 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-B in airway epithelium is sufficient to induce airway hyperresponsiveness and smooth muscle thickening, which are both critical features of allergic airway disease.

Key Words: airway epithelium • nuclear factor-B • inhibitory B kinase-β • airway hyperresponsiveness • smooth muscle cell

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Nuclear factor (NF)-B activation contributes to allergic airway disease, but it is not known whether activation of NF-B in absence of other stimuli is sufficient to cause allergic airway disease. What This Study Adds to the Field This study shows that NF-B activation in airways is sufficient to trigger certain parameters of allergic disease and highlights the potential clinical benefit on focused targeting of the NF-B pathway within the airways.