Exaggerated activation of nuclear factor-kappaB and altered IkappaB-beta processing in cystic fibrosis bronchial epithelial cells.

Venkatakrishnan A, Stecenko AA, King G, Blackwell TR, Brigham KL, Christman JW, Blackwell TS
Am J Respir Cell Mol Biol. 2000 23 (3): 396-403

PMID: 10970832 · DOI:10.1165/ajrcmb.23.3.3949

In cystic fibrosis (CF), inflammatory mediator production by airway epithelial cells is a critical determinant of chronic airway inflammation. To determine whether altered signal transduction through the nuclear factor (NF)-kappaB pathway occurs in CF epithelial cells and results in excessive generation of inflammatory cytokines, we evaluated tumor necrosis factor (TNF)-alpha-induced production of the NF-kappaB-dependent cytokine interleukin (IL)-8 and activation of NF-kappaB in three different human bronchial epithelial cell lines: (1) BEAS cells that express wild-type CF transmembrane conductance regulator (CFTR), (2) IB3 cells with mutant CFTR, and (3) C38 cells, which are "corrected" IB3 cells complemented with wild-type CFTR. Treatment of cells with TNF-alpha (30 ng/ml) resulted in markedly elevated NF-kappaB activation and production of IL-8 by IB3 cells compared with BEAS and C38 cells. Despite the differences in NF- kappaB activation, no differences in basal levels of IkappaB-alpha or TNF-alpha- induced IkappaB-alpha processing and degradation were detected among the cell lines. In contrast, the basal level of IkappaB-beta was increased in the IB3 cells. Treatment with TNF-alpha resulted in increased formation of hypophosphorylated IkappaB-beta and increased nuclear localization of IkappaB-beta in IB3 cells compared with the other cell types. These findings provide additional evidence of a dysregulated inflammatory response in CF.

MeSH Terms (15)

Bronchi Cells, Cultured Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Gene Expression Humans I-kappa B Proteins Immunoblotting Interleukin-8 Ligases Mutagenesis NF-kappa B Phosphorylation Respiratory Mucosa Tumor Necrosis Factor-alpha

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