Ibuprofen modulates NF-kB activity but not IL-8 production in cystic fibrosis respiratory epithelial cells.
BACKGROUND
High-dose ibuprofen is clinically effective in cystic fibrosis (CF); however, its molecular mechanisms are poorly understood.


OBJECTIVE
To test the hypothesis that clinically relevant concentrations of ibuprofen suppress activation of nuclear factor (NF)-kappaB and thus down-regulate stimulated interleukin (IL)-8 production in CF respiratory epithelial cells.


METHODS
The majority of experiments were conducted in CFTE29o- cells (F508del-mutated CF transmembrane regulator, CFTR). Key experiments were confirmed in CFBE41o- cells (F508del-mutated CFTR) and 1HAEo- cells (wild-type CFTR). NF-kappaB and IL-8 were stimulated with tumour necrosis factor (TNF)-alpha or IL-1beta. NF-kappaB and IL-8 suppression by ibuprofen (480 microM) was compared to dexamethasone (5 nM).


RESULTS
Both TNF-alpha and IL-1beta activated NF-kappaB and stimulated IL-8 production. Both ibuprofen and dexamethasone demonstrated comparably modest suppression of NF-kappaB transcriptional activity. However, ibuprofen had no effect on stimulated IL-8 mRNA and protein. By contrast, dexamethasone significantly down-regulated stimulated IL-8 mRNA and protein.


CONCLUSIONS
The present data do not support the hypothesis that ibuprofen down-regulates IL-8 production in response to TNF-alpha and IL-1beta in CF respiratory epithelium. Suppression of NF-kappaB transcriptional activity does not discriminate between anti-inflammatory drugs with or without effects on IL-8 production. We speculate that NF-kappaB-independent mechanisms may be responsible for anti-IL-8 effects of dexamethasone.
Dauletbaev
Nurlan
N
Research Institute, McGill University Health Centre, Montreal Children's Hospital, Montreal, Que., Canada.
Lam
Joyce
J
Eklove
Daniel
D
Iskandar
Michele
M
Lands
Larry C
LC
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology* / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D053583:Interleukin-1beta; D016209:Interleukin-8; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D007052:Ibuprofen