Targeted immunomodulation of the NF-kappaB pathway in airway epithelium impacts host defense against Pseudomonas aeruginosa.
We investigated the impact of inflammatory signaling in airway epithelial cells on host defense against Pseudomonas aeruginosa, a major cause of nosocomial pneumonia. In mice, airway instillation of P. aeruginosa resulted in NF-kappaB activation in the lungs that was primarily localized to the bronchial epithelium at 4 h, but was present in a variety of cell types by 24 h. We modulated NF-kappaB activity in airway epithelium by intratracheal delivery of adenoviral vectors expressing RelA (AdRelA) or a dominant inhibitor of NF-kappaB before P. aeruginosa infection. Bacterial clearance was enhanced by up-regulation of NF-kappaB activity following AdRelA administration and was impaired by treatment with a dominant inhibitor of NF-kappaB. The TNF-alpha concentration in lung lavage was increased by AdRelA treatment and beneficial effects of NF-kappaB up-regulation were abrogated in TNF-alpha-deficient mice. In contrast, NF-kappaB inhibition reduced MIP-2 expression and neutrophil influx following P. aeruginosa infection. Therefore, inflammatory signaling through the NF-kappaB pathway in airway epithelial cells critically regulates the innate immune response to P. aeruginosa.
Department of Veterans Affairs, Nashville, TN 37232, USA. sadikot@uic.edu
Ruxana T
RT
Sadikot
Heng
H
Zeng
Myungsoo
M
Joo
M Brett
MB
Everhart
Taylor P
TP
Sherrill
Bo
B
Li
Dong-sheng
DS
Cheng
Fiona E
FE
Yull
John W
JW
Christman
Timothy S
TS
Blackwell
D000818:Animals; D003428:Cross Infection / Q000276:immunology; D004848:Epithelium / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D017930:Genes, Reporter; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D008156:Luciferases / Q000235:genetics; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000276:immunology* / Q000472:pathogenicity; D015398:Signal Transduction
D018836:Inflammation Mediators; D016328:NF-kappa B; D008156:Luciferases