期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 12, 期 7, 页码 2215-2223出版社
BLACKWELL SCIENCE LTD
DOI: 10.1046/j.1460-9568.2000.00110.x
关键词
brain macrophages; iNOS; MHC class II; NF-kappa B; STAT-1; TNF-alpha
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-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) 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-PGJ(2) 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-PGJ(2) 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-PGJ(2) 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 kappa B, known to mediate IFN-gamma and LPS cell signalling. Our observations suggest that 15d-PGJ(2), 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.
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