Abstract
Incubation of RAW 264.7 murine macrophages with 9,15-dihydroxy-11-oxo-, (5 Z,9α,13 E,15( S))-Prosta-5,13-dien-1-oic acid [prostaglandin D 2 (PGD 2)] induced formation of considerable peroxisome proliferator-activated receptor-γ (PPARγ) activity [Nature 391 (1998) 79]. Because PGD 2 itself is a poor PPARγ ligand, we incubated RAW 264.7 macrophage cultures with prostaglandin D 2 for 24 h and studied the ability of the metabolites formed to activate PPARγ. PGD 2 products were extracted and fractionated by reverse phase high-performance liquid chromatography. Chemical identification was achieved by UV spectroscopy, gas–liquid chromatography/mass spectrometry and chemical syntheses of reference compounds. PGD 2 was converted to eight products, six of which were identified. Ligand-induced interaction of PPARγ with steroid receptor coactivator-1 was determined by glutathione- S-transferase pull-down assays and PPARγ activation was investigated by transient transfection of RAW 264.7 macrophages. In addition to the previously known ligand 11-oxo-(5 Z,9,12 E,14 Z)-Prosta-5,9,12,14-tetraen-1-oic acid (15-deoxy-Δ 12,14-PGJ 2), a novel PPARγ ligand and activator viz. 9-hydroxy-11-oxo-, (5 Z,9α,12 E,14 Z)-Prosta-5,12,14-trien-1-oic acid (15-deoxy-Δ 12,14-PGD 2) was identified. The biological significance of these results is currently under investigation.
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