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Novel keto-phospholipids are generated by monocytes and macrophages, detected in cystic fibrosis, and activate peroxisome proliferator-activated receptor-γ

Hammond, Victoria Jayne, Morgan, Alwena H., Lauder, Sarah Nicol, Thomas, Christopher P., Brown, Sarah, Freeman, Bruce A., Lloyd, Clare M., Davies, Jane, Bush, Andrew, Levonen, Anna-Liisa, Kansanen, Emilia, Villacorta, Luis, Chen, Y. Eugene, Porter, Ned, Garcia-Diaz, Yoel M., Schopfer, Francisco J. and O'Donnell, Valerie Bridget 2012. Novel keto-phospholipids are generated by monocytes and macrophages, detected in cystic fibrosis, and activate peroxisome proliferator-activated receptor-γ. Journal of Biological Chemistry 287 (50) , pp. 41651-41666. 10.1074/jbc.M112.405407

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Abstract

12/15-Lipoxygenases (LOXs) in monocytes and macrophages generate novel phospholipid-esterified eicosanoids. Here, we report the generation of two additional families of related lipids comprising 15-ketoeicosatetraenoic acid (KETE) attached to four phosphatidylethanolamines (PEs). The lipids are generated basally by 15-LOX in IL-4-stimulated monocytes, are elevated on calcium mobilization, and are detected at increased levels in bronchoalveolar lavage fluid from cystic fibrosis patients (3.6 ng/ml of lavage). Murine peritoneal macrophages generate 12-KETE-PEs, which are absent in 12/15-LOX-deficient mice. Inhibition of 15-prostaglandin dehydrogenase prevents their formation from exogenous 15-hydroxyeicosatetraenoic acid-PE in human monocytes. Both human and murine cells also generated analogous hydroperoxyeicosatetraenoic acid-PEs. The electrophilic reactivity of KETE-PEs is shown by their Michael addition to glutathione and cysteine. Lastly, both 15-hydroxyeicosatetraenoic acid-PE and 15-KETE-PE activated peroxisome proliferator-activated receptor-γ reporter activity in macrophages in a dose-dependent manner. In summary, we demonstrate novel peroxisome proliferator-activated receptor-γ-activating oxidized phospholipids generated enzymatically by LOX and 15-prostaglandin dehydrogenase in primary monocytic cells and in a human Th2-related lung disease. The lipids are a new family of bioactive mediators from the 12/15-LOX pathway that may contribute to its known anti-inflammatory actions in vivo.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: eicosanoid, innate immunity, lipoxygenase pathway, macrophages, mass spectrometry (MS), monocytes, phospholipid
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Last Modified: 13 Nov 2017 23:38
URI: http://orca.cf.ac.uk/id/eprint/42035

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