Cytokine-activated bronchial epithelial cell pro-inflammatory functions are effectively downregulated in vitro by ciclesonide.
Ciclesonide, a new inhaled corticosteroid, is administered as a parent compound and converted in the airway mucosa into the active metabolite, desisobutyryl-(des-)ciclesonide. A study was designed to evaluate the ability of ciclesonide to modulate pro-inflammatory functions of human bronchial epithelial cell (HBEC) primary cultures being converted into des-ciclesonide. HBECs were stimulated with interleukin (IL)-4 and tumour necrosis factor (TNF)-alpha (20 ng/mL) in the presence of ciclesonide and intercellular adhesion molecule (ICAM)-1 expression, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-8 release evaluated respectively by FACS and ELISA. Ciclesonide (3 microM) significantly inhibited ICAM-1 expression by stimulated HBECs, already after 3h and still after 48 h culture (p < 0.01). At all the concentrations tested ciclesonide inhibited ICAM-1 expression (p < 0.05). GM-CSF and IL-8 release by stimulated HBECs was also downregulated by ciclesonide (p < 0.05). All the ciclesonide activities tested appeared to be mainly due to a partial inhibition of the 'IL-4 + TNF-alpha-induced' and little or no involvement of the 'constitutive' cell functions. Des-ciclesonide was detected in 24 h culture HBEC supernatants using high-performance liquid chromatography, while no parental compound ciclesonide was present. These results show at cellular level the fast and prolonged activity of ciclesonide on pro-inflammatory functions of HBECs, a selective target of asthma therapy, involved in the activation of this new inhaled corticosteroid.
Silvestri
M
M
Pulmonary Diseases Unit, G. Gaslini Institute, Largo G. Gaslini 5, Genoa, Italy.
Serpero
L
L
Petecchia
L
L
Sabatini
F
F
Cerasoli
F
F
Rossi
G A
GA
D000305:Adrenal Cortex Hormones / Q000378:metabolism / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D011282:Pregnenediones / Q000378:metabolism / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000305:Adrenal Cortex Hormones; D016207:Cytokines; D016209:Interleukin-8; D011282:Pregnenediones; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C120481:ciclesonide