Pseudomonas signal molecule 3-oxo-c12-homoserine lactone interferes with binding of rosiglitazone to human PPARγ

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Title Pseudomonas signal molecule 3-oxo-c12-homoserine lactone interferes with binding of rosiglitazone to human PPARγ
Author Cooley, Margaret A.; Whittall, Christine; Rolph, Michael
Journal Name Microbes and Infection
Year Published 2010
Place of publication France
Publisher Elsevier
Abstract Peroxisome proliferator activated receptor (PPARγ) has been suggested as a target for anti-inflammatory therapy in chronic lung disease, including infection with Pseudomonas aeruginosa. However, the P. aeruginosa signal molecule N-(3-oxo-dodecanoyl)-l-homoserine lactone (3-oxo-C12-HSL) has been reported to inhibit function of PPARs in mammalian cells. This suggests that binding of 3-oxo-C12-HSL to PPARs could increase inflammation during P. aeruginosa infection, particularly if it could compete for binding with other PPAR ligands. We investigated the ability of 3-oxo-C12-HSL to bind to a PPARγ ligand binding domain (LBD) construct, and to compete for binding with the highly active synthetic PPARγ agonist rosiglitazone. We demonstrate that 3-oxo-C12-HSL binds effectively to the PPARγ ligand binding domain, and that concentrations of 3-oxo-C12-HSL as low as 1 nM can effectively interfere with the binding of rosiglitazone to the PPARγ ligand binding domain. Because 3-oxo-C12 HSL has been demonstrated in lungs during P. aeruginosa infection, blockade of PPARγ-dependent signaling by 3-oxo-C12-HSL produced by the infecting P. aeruginosa could exacerbate infection-associated inflammation, and potentially impair the action of PPAR-activating therapy. Thus the proposed use of PPARγ agonists as anti-inflammatory therapy in lung P. aeruginosa infection may depend on their ability to counteract the effects of 3-oxo-C12-HSL.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1016/j.micinf.2009.12.009
Volume 12
Issue Number 3
Page from 231
Page to 237
ISSN 1286-4579
Date Accessioned 2011-03-16
Date Available 2011-03-23T05:46:42Z
Language en_AU
Faculty Faculty of Science, Environment, Engineering and Technology
Subject Bacteriology
URI http://hdl.handle.net/10072/37636
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1x

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