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Infection and Immunity, October 1999, p. 5076-5082, Vol. 67, No. 10
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Pseudomonas aeruginosa Quorum-Sensing Signal Molecule N-(3-Oxododecanoyl)-L-Homoserine Lactone Inhibits Expression of P2Y Receptors in Cystic Fibrosis Tracheal Gland Cells

A. Saleh,1 C. Figarella,1 W. Kammouni,1 S. Marchand-Pinatel,1 A. Lazdunski,2 A. Tubul,3 P. Brun,3 and M. D. Merten1,*

Groupe de Recherche sur les Glandes Exocrines, Faculté de Médecine, 13385 Marseille 05,1 LISM-CNRS, 13402 Marseille Cedex 20,2 Laboratoire de Synthèse Organique Sélective, GCOPL, Associé au CNRS, Faculté des Sciences de Luminy, 13288 Marseille Cedex 9,3 France

Received 6 April 1999/Returned for modification 2 June 1999/Accepted 9 July 1999

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 µM 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.

* Corresponding author. Mailing address: Groupe de Recherche sur les Glandes Exocrines, Faculté de Médecine, 27, Bld Jean Moulin, 13385 Marseille 05, France. Phone: 33(0)4 91788260. Fax: 33(0)491786895. E-mail: grge{at}medecine.univ-mrs.fr.

Infection and Immunity, October 1999, p. 5076-5082, Vol. 67, No. 10
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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