Anti-inflammatory effects of azithromycin in cystic fibrosis airway epithelial cells.
We aimed at identifying molecular mechanisms for anti-inflammatory effects of azithromycin (AZM) suggested by clinical evidences. IL-8 expression and DNA binding activity of two key pro-inflammatory transcription factors (TF), NF-kappaB and AP-1, were investigated in cystic fibrosis (CF) and isogenic non-CF airway epithelial cell lines. AZM reduced about 40% of IL-8 mRNA and protein expression (n=9, p=0.02, and n=4, p=0.00011) in CF cells reaching the levels of non-CF cells. In the presence of AZM we found about 50% and 70% reduction of NF-kappaB and AP-1 DNA binding, respectively (n=3, p=0.01, and n=3, p=0.0017), leading to levels of non-CF cells. The relevance of NF-kappaB and AP-1 in regulating IL-8 promoter transcriptional activity was demonstrated by gene reporter assays (n=4, p=8.54x10(-7), and n=4, p=6.45x10(-6)). Our data support the anti-inflammatory effects of AZM in CF cells, indicating inhibition of transcription of pro-inflammatory genes as possible mechanism, thus providing a rationale for the possible use of specific TF inhibitors for therapy.
Cigana
Cristina
C
Cystic Fibrosis Center, Azienda Ospedaliera di Verona, Piazzale Stefani 1, 37126 Verona, Italy.
Nicolis
Elena
E
Pasetto
Matteo
M
Assael
Baroukh Maurice
BM
Melotti
Paola
P
D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D017963:Azithromycin / Q000008:administration & dosage*; D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D016209:Interleukin-8; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D017963:Azithromycin