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Role of the peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) and its natural ligand 15‐deoxy‐Δ12,14‐prostaglandin J2 in the regulation of microglial functions

The peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) is a member of a large group of nuclear receptors controlling the proliferation of peroxisomes that is involved in the downregulation of macrophage functions. Here, we report that PPAR‐γ was constitutively expressed in rat primary microglial cultures and that such expression was downregulated during microglial activation by endotoxin (LPS). The presence of the PPAR‐γ natural ligand 15‐deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2) counteracted the repression of PPAR‐γ expression caused by LPS. In microglial cultures stimulated by LPS, interferon‐γ (IFN‐γ) or by their combination, 15d‐PGJ2 reduced the production of nitric oxide (NO) and the expression of inducible NO synthase (iNOS). The inhibitory effect was dose‐dependent and did not involve an elevation of cyclic AMP, a second messenger known to inhibit NOS expression in microglia. In addition, 15d‐PGJ2 down‐regulated other microglial functions, such as tumour necrosis factor‐α (TNF‐α) synthesis and major histocompatibility complex class II (MHC class II) expression. The effects of 15d‐PGJ2 occurred, at least in part, through the repression of two important transcription factors, the signal transducer and activator of transcription 1 and the nuclear factor κB, known to mediate IFN‐γ and LPS cell signalling. Our observations suggest that 15d‐PGJ2, the synthesis of which is likely to occur within the brain, could play an important role in preventing brain damage associated with excessive microglial activation.