Selective I kappa B kinase expression in airway epithelium generates neutrophilic lung inflammation.

Abstract

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.

• Authors: Ruxana T Sadikot, Wei Han, M Brett Everhart, Ornella Zoia, R Stokes Peebles, E Duco Jansen, Fiona E Yull, John W Christman, Timothy S Blackwell
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 170 Issue 2 Pg. 1091-8 (Jan 15 2003) ISSN: 0022-1767 [Print] United States
• PMID: 12517978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cytokines
• NF-kappa B
• Protein Serine-Threonine Kinases
• Chuk protein, mouse
• I-kappa B Kinase
• Ikbkb protein, mouse
• Ikbke protein, mouse

Topics

• Adenoviridae (genetics)
• Animals
• Cytokines (biosynthesis)
• Gene Expression Regulation, Viral
• Genetic Vectors (administration & dosage)
• I-kappa B Kinase
• Inflammation (enzymology, immunology, metabolism)
• Intubation, Intratracheal
• Lung (enzymology, immunology, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Transgenic
• NF-kappa B (metabolism)
• Neutrophils (pathology)
• Protein Serine-Threonine Kinases (biosynthesis, physiology)
• Respiratory Mucosa (enzymology, metabolism)
• Transcriptional Activation (immunology)
• Transgenes
• Virus Replication (genetics)