Genistein inhibits constitutive and inducible NF kappa B activation and decreases IL-8 production by human cystic fibrosis bronchial gland cells

The inflammatory pathogenesis in airways of patients with cystic fibrosis ( CF) is still unresolved. We demonstrate here that in in situ human Delta F5 08 homozygous CF bronchial tissues, submucosal gland cells exhibit an absen ce of inhibitor factor kappa B alpha (I kappa B alpha) and high levels of c hemokine interleukin-8 (IL-8) expression. These results were confirmed by c ultured human CF bronchial gland cells in which a lack of cytosolic I kappa B alpha and high levels of constitutively activated nuclear factor kappa B (NF kappa B) associated with an up-regulation of IL-8 production (13-fold increase) were found when compared to non-CF (control) disease bronchial gl and cells. We also demonstrated that the isoflavone genistein, a well known CFTR mutant Cl- channel stimulator, significantly reduces the endogenous a nd Pseudomonas aeruginosa lipopolysaccharide-induced IL-8 production in cul tured CF bronchial gland cells by increasing cytosolic I kappa B alpha prot ein levels. Overall, results show that genistein is a potent inhibitor of t he activated NF kappa B identified in CF gland cells. This strong inhibitio n of constitutively activated NF kappa B and the resulting down-regulation of IL-8 production by genistein in the CF gland cells highlights the key ro le played by cytosolic I kappa B alpha in the regulation of inflammatory pr ocesses in CF human airway cells.