Details

Autor(en) / Beteiligte

• Hammond, Victoria J.
• Morgan, Alwena H.
• Lauder, Sarah
• 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.
• O'Donnell, Valerie B.

Titel

Novel Keto-phospholipids Are Generated by Monocytes and Macrophages, Detected in Cystic Fibrosis, and Activate Peroxisome Proliferator-activated Receptor-γ

Ist Teil von

• The Journal of biological chemistry, 2012-12, Vol.287 (50), p.41651-41666

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2012

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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. Background: Lipoxygenases (LOXs) generate eicosanoids in inflammation. Results: Monocyte/macrophage LOXs generate novel phospholipid-esterified eicosanoids containing ketoeicosatetraenoic acid or hydroperoxyeicosatetraenoic acid. They activate peroxisome proliferator-activated receptor-γ transcriptional activity and are found in cystic fibrosis bronchoalveolar fluid. Significance: LOXs generate esterified eicosanoids in vitro and in vivo. Conclusion: These new lipids represent new families of bioactive mediators.