15d-PGJ2 inhibits oxidized LDL-induced macrophage proliferation by inhibition of GM-CSF production via inactivation of NF-κB

Macrophage-derived foam cells play an important role in atherosclerotic lesions. Oxidized low-density lipoprotein (Ox-LDL) induces macrophage proliferation via production of GM-CSF in vitro. This study investigated the effects of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a natural ligand for peroxisome proliferator-activated receptor γ, on macrophage proliferation. Mouse peritoneal macrophages and RAW264.7 cells were used for proliferation study and reporter gene assay, respectively. Twenty microgram per milliliter of Ox-LDL induced [3H]thymidine incorporation in mouse peritoneal macrophages, and 15d-PGJ2 inhibited Ox-LDL-induced [3H]thymidine incorporation in a dose-dependent manner. Ox-LDL increased GM-CSF release and GM-CSF mRNA expression, and activated GM-CSF gene promoter, all of which were prevented by 15d-PGJ2 or 2-cyclopenten-1-one, a cyclopentenone ring of 15d-PGJ2. The suppression of GM-CSF promoter activity by 15d-PGJ2 and 2-cyclopenten-1-one was mediated through reduction of NF-κB binding to GM-CSF promoter. These results suggest that 15d-PGJ2 inhibits Ox-LDL-induced macrophage proliferation through suppression of GM-CSF production via NF-κB inactivation.