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Published ahead of print on February 10, 2005, doi:10.1165/rcmb.2004-0274OC

Am. J. Respir. Cell Mol. Biol., Volume 32, Number 5, May 2005, 411-419

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Submitted on August 26, 2004
Revised on February 10, 2005

Pseudomonas aeruginosa elastase disables PAR2 in respiratory epithelial cells

Sophie Dulon1, Dominique Leduc1, Graeme S Cottrell2, Jacques D'Alayer3, Kristina K Hansen4, Nigel W Bunnett2, Morley D Hollenberg4, Dominique Pidard1, and Michel Chignard1*

1 Defense innee et inflammation, Institut Pasteur, Paris, France, 2 Departments of Surgery and Physiology, University of California, San Francisco, San Francisco, California, USA, 3 Plateforme d'Analyse et de Microsequencage des Proteines, Institut Pasteur, Paris, France, 4 Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada

* To whom correspondence should be addressed. E-mail: chignard{at}pasteur.fr.

Pseudomonas aeruginosa, a major lung pathogen in cystic fibrosis (CF) patients, secretes an elastolytic metalloproteinase (EPa) contributing to bacterial pathogenicity. Proteinase-activated receptor 2 (PAR2), implicated in the pulmonary innate defense, is activated by the cleavage of its extracellular N-terminal domain, unmasking a new N-terminal sequence starting with SLIGKV, which binds intramolecularly and activates PAR2. We show that EPa cleaves the N-terminal domain of PAR2 from the cell surface without triggering receptor endocytosis as trypsin does. As evaluated by measurements of cytosolic calcium as well as PGE2 and IL-8 production, this cleavage does not activate PAR2, but rather disarms the receptor for subsequent activation by trypsin, but not by the synthetic receptor-activating peptide, SLIGKV-NH2. Proteolysis by EPa of synthetic peptides representing the N-terminal cleavage/activation sequences of either human or rat PAR2 indicates that cleavages resulting from EPa activity would not produce receptor-activating tethered ligands, but would disarm PAR2 in regard to any further activating proteolysis by activating proteinases. Our data indicate that a pathogen-derived proteinase like EPa can potentially silence the function of PAR2 in the respiratory tract, thereby altering the host innate defense mechanisms and respiratory functions, thus contributing to pathogenesis in the setting of a disease like CF.




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