ATP and
UTP have been proposed for use as therapeutic treatment of the abnormal ion transport in the airway epithelium in
cystic fibrosis (CF), the most characteristic feature of which is permanent
infection by Pseudomonas aeruginosa. As for diverse gram-negative bacteria, this pathogenic bacterium accumulates diffusible N-acylhomoserine
lactone (AHL) signal molecules, and when a threshold concentration is reached,
virulence factor genes are activated. Human submucosal tracheal gland serous (HTGS) cells are believed to play a major role in the physiopathology of CF. Since
ATP and
UTP stimulate CF epithelial cells through P2Y receptors, we sought to determine whether CF HTGS cells are capable of responding to the AHLs
N-butanoyl-L-homoserine lactone (BHL),
N-hexanoyl-L-homoserine lactone (HHL),
N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL), and N-(3-oxohexanoyl)-L-homoserine
lactone (OHHL), with special reference to P2Y receptors. All AHLs inhibited
ATP- and
UTP-induced secretion by CF HTGS cells. The 50% inhibitory concentrations were as high as 10 and 5 microM for BHL and HHL, respectively, but were only 0.3 and 0.4 pM for OdDHL and OHHL, respectively. Furthermore, all AHLs down-regulated the expression of the P2Y2 and
P2Y4 receptors.
Ibuprofen and
nordihydroguaiaretic acid were able to prevent AHL inhibition of the responses to
nucleotides, but neither
dexamethasone nor
indomethacin was able to do this. These data indicate that AHLs may alter responsiveness to
ATP and
UTP by CF HTGS cells and suggest that, in addition to
ATP and/or
UTP analogues,
ibuprofen may be of use for a combinational pharmacological
therapy for CF.