Role of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and its natural ligand 15-deoxy-Delta12, 14-prostaglandin J2 in the regulation of microglial functions.
The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) 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-gamma 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-gamma natural ligand 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) counteracted the repression of PPAR-gamma expression caused by LPS. In microglial cultures stimulated by LPS, interferon-gamma (IFN-gamma) 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-alpha (TNF-alpha) 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 kappaB, known to mediate IFN-gamma 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.
Bernardo
A
A
Neurobiology Section, Laboratory of Pathophysiology, Istituto Superiore di Sanità, Rome, Italy.
Levi
G
G
Minghetti
L
L
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D015232:Dinoprostone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D016328:NF-kappa B / Q000096:biosynthesis; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis; D014157:Transcription Factors / Q000032:analysis / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000067956:Adenylyl Cyclase Inhibitors; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C017759:9-(tetrahydro-2-furyl)-adenine; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000225:Adenine; D015232:Dinoprostone; D015230:Prostaglandin D2