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

J Biol Chem. 2012 Dec 7;287(50):41651-66. doi: 10.1074/jbc.M112.405407. Epub 2012 Oct 11.

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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonate 12-Lipoxygenase / metabolism
  • Arachidonate 15-Lipoxygenase / metabolism
  • Arachidonic Acids / metabolism
  • Cystic Fibrosis / metabolism*
  • Cystic Fibrosis / pathology
  • Female
  • Humans
  • Macrophages, Alveolar / metabolism*
  • Macrophages, Alveolar / pathology
  • Macrophages, Peritoneal / metabolism*
  • Macrophages, Peritoneal / pathology
  • Male
  • Mice
  • Monocytes / metabolism*
  • Monocytes / pathology
  • PPAR gamma / metabolism*
  • Phosphatidylethanolamines / metabolism*

Substances

  • Arachidonic Acids
  • PPAR gamma
  • Phosphatidylethanolamines
  • Arachidonate 12-Lipoxygenase
  • Arachidonate 15-Lipoxygenase