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We have previously reported that rat primary microglial cultures express the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) and that several functions associated with the activation of these cells, including nitric oxide (NO) and tumor necrosis factor-α synthesis, are down-regulated by 15-deoxy-Δ12,14 -prostaglandin J2 (15d-PGJ2 ) and ciglitazone, two specific PPAR-γ agonists. Here we demonstrate that microglial cells not only express a functionally active PPAR-γ, but also synthesize large amounts of 15d-PGJ2 upon stimulation with lipopolysaccharide (LPS). In addition, we show that, although 15d-PGJ2 and ciglitazone were equally effective in reducing microglial activation when used at 1–5 µ m concentrations, 15d-PGJ2 , but not of ciglitazone, reduced PGE2 production at low concentration (0.1 µ m ) and induced a time-dependent microglial impairment and apoptosis at high concentration (10 µ m ). Interestingly, the inhibition of PGE2 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-PGJ2 affects the functional state and the survival of activated microglia through mechanisms only in part dependent on PPAR-γ and that the concentration of 15d-PGJ2 is crucial in determining the particular microglial function affected. [ABSTRACT FROM AUTHOR]

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-delta12,14-prostaglandin J2 (15d-PGJ2) 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-PGJ2 upon stimulation with lipopolysaccharide (LPS). In addition, we show that, although 15d-PGJ2 and ciglitazone were equally effective in reducing microglial activation when used at 1-5 microm concentrations, 15d-PGJ2, but not of ciglitazone, reduced PGE2 production at low concentration (0.1 microm) and induced a time-dependent microglial impairment and apoptosis at high concentration (10 microm). Interestingly, the inhibition of PGE2 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-PGJ2 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-PGJ2 is crucial in determining the particular microglial function affected.