Selective I kappa B kinase expression in airway epithelium generates neutrophilic lung inflammation.
To determine whether NF-kappaB activation is sufficient to generate lung inflammation in vivo, we selectively expressed a constitutively active form of IkappaB kinase 1 (cIKK1) or IkappaB 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-kappaB-dependent promoter, we detected significantly increased luciferase activity over time (up to 96 h). Compared with control mice treated with adenoviral vectors expressing beta-galactosidase, lung bioluminescence and tissue luciferase activity were increased in NF-kappaB reporter mice treated with adenovirus (Ad)-cIKK1 or Ad-cIKK2. NF-kappaB 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-kappaB-dependent chemokines macrophage-inflammatory protein 2 and KC and increased numbers of neutrophils. Coadministration of adenoviral vectors expressing a transdominant inhibitor of NF-kappaB with Ad-cIKK1 or Ad-cIKK2 resulted in abrogated NF-kappaB activation and other parameters of lung inflammation, demonstrating that the observed inflammatory effects of Ad-cIKK1 and Ad-cIKK2 were dependent on NF-kappaB activation by these kinases. These data show that selective expression of IkappaB kinases in airway epithelium results in NF-kappaB activation, inflammatory mediator production, and neutrophilic lung inflammation. Therapies targeted to NF-kappaB in lung epithelium may be beneficial in treating inflammatory lung diseases.
Sadikot
Ruxana T
RT
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Han
Wei
W
Everhart
M Brett
MB
Zoia
Ornella
O
Peebles
R Stokes
RS
Jansen
E Duco
ED
Yull
Fiona E
FE
Christman
John W
JW
Blackwell
Timothy S
TS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors / Q000008:administration & dosage; D051550:I-kappa B Kinase; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D007442:Intubation, Intratracheal; D008168:Lung / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000502:physiology; D020545:Respiratory Mucosa / Q000201:enzymology* / Q000378:metabolism; D015533:Transcriptional Activation / Q000276:immunology; D019076:Transgenes; D014779:Virus Replication / Q000235:genetics
D016207:Cytokines; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse