Genistein inhibits constitutive and inducible NFκB 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 F508 homozygous CF bronchial tissues, submucosal gland cells exhibit an absence of inhibitor factor kappa B alpha (I kappa B alpha) and high levels of chemokine interleukin-8 (IL-8) expression. These results were confirmed by cultured 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 gland cells. We also demonstrated that the isoflavone genistein, a well known CFTR mutant Cl- channel stimulator, significantly reduces the endogenous and Pseudomonas aeruginosa lipopolysaccharide-induced IL-8 production in cultured CF bronchial gland cells by increasing cytosolic I kappa B alpha protein levels. Overall, results show that genistein is a potent inhibitor of the activated NF kappa B identified in CF gland cells. This strong inhibition 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 role played by cytosolic I kappa B alpha in the regulation of inflammatory processes in CF human airway cells.