Pseudomonas signal molecule 3-oxo-C12-homoserine lactone interferes with binding of rosiglitazone to human PPARgamma.

Abstract

Peroxisome proliferator activated receptor (PPARgamma) 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 PPARgamma ligand binding domain (LBD) construct, and to compete for binding with the highly active synthetic PPARgamma agonist rosiglitazone. We demonstrate that 3-oxo-C12-HSL binds effectively to the PPARgamma 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 PPARgamma ligand binding domain. Because 3-oxo-C12 HSL has been demonstrated in lungs during P. aeruginosa infection, blockade of PPARgamma-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 PPARgamma agonists as anti-inflammatory therapy in lung P. aeruginosa infection may depend on their ability to counteract the effects of 3-oxo-C12-HSL.

• Authors: Margaret A Cooley, Christine Whittall, Michael S Rolph
• Journal: Microbes and infection (Microbes Infect) Vol. 12 Issue 3 Pg. 231-7 (Mar 2010) ISSN: 1769-714X [Electronic] France
• PMID: 20074659 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Masson SAS. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• N-(3-oxododecanoyl)homoserine lactone
• PPAR gamma
• Thiazolidinediones
• Rosiglitazone
• Homoserine
• 4-Butyrolactone

Topics

• 4-Butyrolactone (analogs & derivatives, metabolism)
• Anti-Inflammatory Agents (antagonists & inhibitors)
• Homoserine (analogs & derivatives, metabolism)
• Humans
• PPAR gamma (metabolism)
• Protein Binding
• Pseudomonas aeruginosa (pathogenicity)
• Rosiglitazone
• Thiazolidinediones (antagonists & inhibitors)