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(American Journal of Pathology. 1999;155:473-481.)
© 1999 American Society for Investigative Pathology

Regular Articles

Genistein Inhibits Constitutive and Inducible NF{kappa}B Activation and Decreases IL-8 Production by Human Cystic Fibrosis Bronchial Gland Cells

Olivier Tabary*, Sandie Escotte*, Jean Paul Couetil{dagger}, Dominique Hubert{ddagger}, Daniel Dusser{ddagger}, Edith Puchelle* and Jacky Jacquot*

From INSERM Unité 514,*
Reims; the Département de Chirurgie Cardio-Vasculaire,{dagger}
Hôpital Broussais, Paris; and the Service de Pneumologie,{ddagger}
Hôpital Cochin, Paris, France

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.




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Copyright © 1999 by the American Society for Investigative Pathology.