Relationship between I kappa B alpha deficiency, NF kappa B activity and interleukin-8 production in CF human airway epithelial cells

Several recent reports have suggested that airway inflammation may precede infection and relate to an endogenous dysregulation of pro-inflammatory cytokines in cystic fibrosis (CF) airways. Evidence suggests that activation of the nuclear factor kappa B (NF kappaB), which regulates the inflammatory gene transcription, depends on the degradation of the inhibitory factor I kappaB alpha. We show that, in in situ human Delta F508 CF bronchial tissues, inhibitor factor I kappaB alpha is not present in gland cells, although endogenous levels of chemokine IL-8 are high. These data are confirmed by studying cultured CF human bronchial gland cells, in which a lack of cytosolic I kappaB alpha. and high levels of activated NF kappaB, concomitant with IL-8 overproduction (a 13-fold increase) are found when compared to non-CF bronchial gland cells. Interestingly, treatment of CF gland cells with the isoflavone genistein, a well known CFTR mutant Cl- channel stimulator, results in a significant decrease (P <0.001) in IL-8 production down to levels released by non-CF gland cells. The addition of genistein also reverses the effects of lipopolysaccharide (LPS) Pseudomonas-aeruginosa-induced nuclear translocation of NF kappaB by increasing I kappaB alpha protein level (65%) in CF gland cells. Our data indicate that the induction of I kappaB alpha protein in CF airway glandular epithelial cells may be a novel mechanism by which IL-8-mediated lung inflammatory events are markedly reduced in CF patients, at least at the airway glandular level.