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

Margaret Cooley, Christine Whittall, Michael Rolph

Research output: Contribution to journalArticle

27 Citations (Scopus)

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
Original languageEnglish
Pages (from-to)231-237
Number of pages7
JournalMicrobes and Infection
Volume12
Issue number3
DOIs
Publication statusPublished - 2010
Externally publishedYes

Fingerprint

rosiglitazone
Peroxisome Proliferator-Activated Receptors
PPAR gamma
Pseudomonas
Pseudomonas aeruginosa
Pseudomonas Infections
Ligands
homoserine lactone
Anti-Inflammatory Agents
Inflammation

Cite this

Cooley, Margaret ; Whittall, Christine ; Rolph, Michael. / Pseudomonas signal molecule 3-oxo-C12-homoserine lactone interferes with binding of rosiglitazone to human PPARgamma. In: Microbes and Infection. 2010 ; Vol. 12, No. 3. pp. 231-237.
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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",
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Pseudomonas signal molecule 3-oxo-C12-homoserine lactone interferes with binding of rosiglitazone to human PPARgamma. / Cooley, Margaret; Whittall, Christine; Rolph, Michael.

In: Microbes and Infection, Vol. 12, No. 3, 2010, p. 231-237.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pseudomonas signal molecule 3-oxo-C12-homoserine lactone interferes with binding of rosiglitazone to human PPARgamma.

AU - Cooley, Margaret

AU - Whittall, Christine

AU - Rolph, Michael

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N2 - 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

AB - 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

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