Pseudomonas signal molecule 3-oxo-C12-homoserine lactone interferes with binding of rosiglitazone to human PPARγ |
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| Authors: | Margaret A Cooley Christine Whittall Michael S Rolph |
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| Institution: | 1. Menzies Research Institute, University of Tasmania, Private Bag 73, Hobart TAS 7000, Australia;2. School of Biotechnology and Biomolecular Sciences, University of NSW, Sydney 2052, Australia;3. Garvan Institute of Medical Research, Sydney, Australia;1. Department of Pharmaceutical Science and Research, School of Pharmacy, Marshall University, Huntington, WV 25755, United States;2. Department of Biochemistry and Microbiology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States;3. Department of Pediatrics, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States;4. Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, KY 40506, United States;5. Progenesis Technologies, LLC, Huntington, WV 25755, United States;1. Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi''an, 710069, China;2. Department of Oral Biology; Department of Medical Microbiology, University of Manitoba, 780 Bannatyne Ave., Winnipeg, MB, R3E 0W2, Canada;1. Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan;2. Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan;3. Laboratory of Organic Chemistry, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba, Japan;4. Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan;5. Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashina, Kyoto, Japan |
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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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