Exaggerated activation of nuclear factor-kappa B and altered I kappa B-beta processing in cystic fibrosis bronchial epithelial cells

In cystic fibrosis (CF), inflammatory mediator production by airway epithel ial cells is a critical determinant of chronic airway inflammation. To dete rmine whether altered signal transduction through the nuclear factor (NF)-k appa B pathway occurs in CF epithelial cells and results in excessive gener ation of inflammatory cytokines, we evaluated tumor necrosis factor (TNF)-a lpha-induced production of the NF-kappa B-dependent cytokine interleukin (I L)-8 and activation of NF-KB in three different human bronchial epithelial cell lines: (1) BEAS cells that express wild-type CF transmembrane conducta nce regulator (CFTR), (2) IB3 cells with mutant CFTR, and (3) C38 cells, wh ich are "corrected" IB3 cells complemented with wild-type CFTR, Treatment o f cells with TNF-alpha (30 ng/ml) resulted in markedly elevated NF-kappa B activation and production of IL-8 by IB3 cells compared with BEAS and C38 c ells. Despite the differences in NF-kappa B activation, no differences in b asal levels of I kappa B-alpha or TNF-alpha-induced I kappa B-alpha process ing and degradation were detected among the cell lines. In contrast, the ba sal level of I kappa B-beta was increased in the IB3 cells. Treatment with TNF-alpha resulted in increased formation of hypophosphorylated I kappa B-b eta and increased nuclear localization of I kappa B-beta in IB3 cells compa red with the other cell types, These findings provide additional evidence o f a dysregulated inflammatory response in CF.