Peroxisome proliferator-activated receptor agonists prevent 25-OH-cholesterol induced c-jun activation and cell death

BACKGROUND: Cholesterol oxides, the oxygenated derivatives of cholesterol, have been shown to cause programmed cell death in a variety of cell types. Using N9 microglia, this study was designed to investigate the molecular events induced by cholesterol oxides prior to the execution of programmed cell death. RESULTS: Microglia were very sensitive to 25-OH-cholesterol, such that a 2-day treatment of the cells with 5 μM 25-OH-cholesterol reduced cell viability to 5–10% of controls. There was a dose- and time-dependent increase in c-jun and phospho-c-jun levels in microglia prior to this 25-OH-cholesterol induced cell death. In contrast, 7-β-OH-cholesterol, which was relatively non-toxic to microglia, did not increase phospho-c-jun levels. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that have important roles in atherogenesis. Results from this study indicate that PPAR agonists such as 15d-PGJ(2), indomethacin and WY14643 can attenuate cholesterol oxide induced c-jun activation and cell death in microglia. CONCLUSIONS: Peroxisome proliferator-activated receptor agonists may be useful in future development of pharmacological agents against cholesterol oxide induced cytotoxicity.