15-Deoxy-Δ12,14-prostaglandin J2 regulates the functional state and the survival of microglial cells through multiple molecular mechanisms

We have previously reported that rat primary microglial cultures express the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and that several functions associated with the activation of these cells, including nitric oxide (NO) and tumor necrosis factor-alpha synthesis, are down-regulated by 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and ciglitazone, two specific PPAR-gamma agonists. Here we demonstrate that microglial cells not only express a functionally active PPAR-gamma, but also synthesize large amounts of 15d-PGJ(2) upon stimulation with lipopolysaccharide (LPS). In addition, we show that, although 15d-PGJ(2) and ciglitazone were equally effective in reducing microglial activation when used at 1-5 mum concentrations, 15d-PGJ(2), but not of ciglitazone, reduced PGE(2) production at low concentration (0.1 mum) and induced a time-dependent microglial impairment and apoptosis at high concentration (10 mum). Interestingly, the inhibition of PGE(2) production was achieved mainly through the inhibition of cycloxygenase-2 enzymatic activity, as the expression of this enzyme and that of the microsomal isoform of PGE synthase remained unaltered. These findings suggest that 15d-PGJ(2) affects the functional state and the survival of activated microglia through mechanisms only in part dependent on PPAR-gamma and that the concentration of 15d-PGJ(2) is crucial in determining the particular microglial function affected.