Novel keto-phospholipids are generated by monocytes and macrophages, detected in cystic fibrosis, and activate peroxisome proliferator-activated receptor-γ.
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.
School of Medicine, Cardiff University, Heath Park Campus, Cardiff CF14 4XN, United Kingdom.
Victoria J
VJ
Hammond
Alwena H
AH
Morgan
Sarah
S
Lauder
Christopher P
CP
Thomas
Sarah
S
Brown
Bruce A
BA
Freeman
Clare M
CM
Lloyd
Jane
J
Davies
Andrew
A
Bush
Anna-Liisa
AL
Levonen
Emilia
E
Kansanen
Luis
L
Villacorta
Y Eugene
YE
Chen
Ned
N
Porter
Yoel M
YM
Garcia-Diaz
Francisco J
FJ
Schopfer
Valerie B
VB
O'Donnell
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D001095:Arachidonic Acids / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000378:metabolism*
D001095:Arachidonic Acids; D047495:PPAR gamma; D010714:Phosphatidylethanolamines; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase