Abstract
The peroxisome proliferator‐activated receptor γ (PPARγ) is a member of a large group of nuclear receptors controlling lipid and glucose metabolism, energy homeostasis, adipose cell and macrophage differentiation. We have recently shown that PPARγ is constitutively expressed in rat primary microglial cultures and is down regulated during microglial activation by endotoxin (LPS), suggesting that this receptor could play an important role in controlling microglial activation. To verify this hypothesis, we have studied the effects of the PPARγ natural ligand 15d‐PGJ2 on several functions associated with microglial activation. In microglial cultures stimulated by LPS, interferon‐γ or by their combination, 1–5 µM 15d‐PGJ2 reduced the production of nitric oxide (NO) and the expression of inducible NO synthase, the synthesis of tumour necrosis factoralfa and the expression of MHC‐II antiogens. The effects of 15d‐PGJ2 occurred through the repression of the transcription factors, STAT‐1 and NF‐kB, and were mimicked by ciglitazone, a synthetic PPARγ agonist, suggesting the involvement of PPARγ. At lower concentrations 15d‐PGJ2, but not ciglitazone, reduced the LPS‐induced PGE2 production, suggesting that PPARγ independent mechanism(s) could contribute to this inhibitory activity. Finally, at high concentration (10 µM) 15d‐PGJ2 induced a time‐dependent mitochondrial impairment which was paralleled by an increased number of apoptotic and necrotic microglial cells. Altogether, our observations strongly suggest that 15d‐PGJ2, which is synthesised by LPS‐ activated microglia, is able to regulate the brain inflammatory response through multiple mechanisms affecting the functional state and the survival of activated microglia.
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