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B Kinase Expression in Airway Epithelium Generates Neutrophilic Lung Inflammation1
* Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Departments of
Cell and Developmental Biology,
Biomedical Engineering, and
Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232; and
¶ Department of Veterans Affairs Medical Center, Nashville, TN 37212
To determine whether NF-
B activation is sufficient to generate
lung inflammation in vivo, we selectively expressed a constitutively
active form of IB kinase 1 (cIKK1) or IB kinase 2 (cIKK2) in
airway epithelium. After intratracheal administration of adenoviral
vectors expressing cIKK1 or cIKK2 to transgenic reporter mice that
express Photinus luciferase under the control of an
NF-B-dependent promoter, we detected significantly increased
luciferase activity over time (up to 96 h). Compared with control
mice treated with adenoviral vectors expressing 
-galactosidase, lung
bioluminescence and tissue luciferase activity were increased in
NF-B reporter mice treated with adenovirus (Ad)-cIKK1 or
Ad-cIKK2. NF-B activation in lungs of Ad-cIKK1- and Ad-cIKK2-treated
mice was confirmed by immunoblots for RelA and EMSA from lung nuclear
protein extracts. Mice treated with Ad-cIKK1 or Ad-cIKK2 showed
induction of mRNA expression of several chemokines and cytokines in
lung tissue. In lung lavage fluid, mice treated with Ad-cIKK1 or
Ad-cIKK2 showed elevated concentrations of NF-B-dependent chemokines
macrophage-inflammatory protein 2 and KC and increased numbers
of neutrophils. Coadministration of adenoviral vectors expressing a
transdominant inhibitor of NF-B with Ad-cIKK1 or Ad-cIKK2 resulted
in abrogated NF-B activation and other parameters of lung
inflammation, demonstrating that the observed inflammatory effects of
Ad-cIKK1 and Ad-cIKK2 were dependent on NF-B activation by these
kinases. These data show that selective expression of IB kinases in
airway epithelium results in NF-B activation, inflammatory mediator
production, and neutrophilic lung inflammation. Therapies targeted to
NF-B in lung epithelium may be beneficial in treating inflammatory
lung diseases.
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