title: 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.affiliation: Menzies Research Institute, University of Tasmania, Private Bag 73, Hobart TAS 7000, Australia. margaret.cooley@utas.edu.au
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Cooley
authors.forename: Christine
authors.initials: C
authors.lastname: Whittall
authors.forename: Michael S
authors.initials: MS
authors.lastname: Rolph
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000037:antagonists & inhibitors*; D006714:Homoserine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D047495:PPAR gamma / Q000378:metabolism*; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000037:antagonists & inhibitors*
chemical_list: D000893:Anti-Inflammatory Agents; C109860:N-(3-oxododecanoyl)homoserine lactone; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D006714:Homoserine; D015107:4-Butyrolactone