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B activation and sustained IL-8 gene expression in primary cultures of cystic fibrosis airway epithelial cells stimulated with Pseudomonas aeruginosa
1 Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
2 Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
* To whom correspondence should be addressed. E-mail: ferkol_t{at}kids.wustl.edu.
The progression of lung disease in cystic fibrosis (CF) is characterized by an exuberant inflammatory response mounted by the respiratory epithelium that is further exacerbated
by bacterial infection. Recent studies have demonstrated up-regulation of nuclear factor-kappa B (NF-
B) in response to infection in genetically modified cell culture
models, which is associated with expression of interleukin (IL)-8. Using human airway epithelial cells grown in primary culture we examined in vitro activation of NF-B in cells isolated from five CF (
F508/F508) and three non-CF (NCF) patients in response to Pseudomonas aeruginosa. Immunofluorescence, gel-shift and immunoblot assays demonstrated a rapid translocation of NF-B subunits (p50 and p65) to the nucleus in both CF and NCF cell cultures. However, nuclear extracts from CF cells both before and
following P. aeruginosa stimulation revealed elevated NF-B activation compared to
NCF cells. Additionally, elevated nuclear levels of the NF-B inhibitor IB
were detected in nuclei of CF cells after P. aeruginosa stimulation but this increase was transient. There was no difference in IL-8 mRNA levels between CF and NCF cells early after stimulation, whereas expression was higher and sustained in CF cells at later times. Our results also demonstrated increased baseline translocation of NF-B to
nuclei of primary CF epithelial cell cultures, but intranuclear IB may initially block its
effects following P. aeruginosa stimulation. Thus, IL-8 mRNA expression was prolonged after P. aeruginosa stimulation in CF epithelial cells and this sustained IL-8 expression may contribute to the excessive inflammatory response in CF.
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