Fluticasone reduces IL-6 and IL-8 production of cystic fibrosis bronchial epithelial cells via IKK-beta kinase pathway.
Inhaled fluticasone propionate (FP) is widely used to reduce pulmonary inflammation in chronic obstructive pulmonary disease, but the potential effects of FP on airway epithelial cells from patients with cystic fibrosis (CF) are unknown. In CF disease, a nonregulated inflammatory lung response occurs through exaggerated nuclear factor (NF)-kappaB activation and elevated pro-inflammatory cytokines production by airway epithelial cells. To determine whether FP reduces cytokine production in bronchial epithelial cells via NF-kappaB, the authors investigated the nonstimulated and the Pseudomonas aeruginosa lipopolysaccharide (LPS) stimulated production of NF-kappaB-dependent interleukin (IL)-6, IL-8 and RANTES (regulated on activation, T-cell expressed and secreted) along with the activation of NF-kappaB in non-CF and CF human bronchial gland epithelial cells. It was demonstrated that a relevant concentration of FP (10(-8) M) inhibited constitutive and P. aeruginosa LPS-induced IL-6 and IL-8 production of non-CF and CF bronchial epithelial cells. Interestingly, the expression of two IkappaB kinases (IKK)-alpha/beta, the degradation of cytosolic IkappaB-beta inhibitor and the NF-kappaB deoxyribonucleic acid binding activity were markedly reduced after FP treatment in both CF and non-CF bronchial epithelial cells. It was shown by the authors that fluticasone propionate exerts an anti-inflammatory effect by blocking a signal transduction leading to a reduced level of IkappaB-alpha/beta kinases in bronchial epithelial cells. In particular the strong effect on the IkappaB-beta kinase, which is known to be elevated in bronchial epithelial cells in cystic fibrosis patients, was observed.
Escotte
S
S
INSERM UMRS 514, IFR 53, CHU Maison Blanche, Reims Cedex, France.
Tabary
O
O
Dusser
D
D
Majer-Teboul
C
C
Puchelle
E
E
Jacquot
J
J
D000704:Analysis of Variance; D000730:Androstadienes / Q000494:pharmacology*; D015153:Blotting, Western; D001980:Bronchi / Q000473:pathology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000068298:Fluticasone; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
D000730:Androstadienes; D001993:Bronchodilator Agents; D018946:Chemokine CCL5; D018925:Chemokines; D000068298:Fluticasone; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C083487:I kappa B beta protein; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human