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
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
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DOI：
10.1046/j.1460-9568.2000.00110.x
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发表时间：
2000-07-01
影响因子：
3.4
通讯作者：
Minghetti, L
中科院分区：
文献类型：
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作者：
Bernardo, A;Levi, G;Minghetti, L
过氧化物酶体增殖物激活受体-γ（PPAR-gamma）是控制参与巨噬细胞功能下调的过氧化物酶体增殖的一大组核受体的成员。在这里，我们报告说，PPAR-gamma组成型表达在大鼠原代小胶质细胞培养，这种表达下调小胶质细胞激活内毒素（LPS）。PPAR-gamma天然配体15-脱氧-Delta（12，14）-前列腺素J（2）（15 d-PGJ（2））的存在抵消了LPS引起的PPAR-gamma表达的抑制。在由LPS、干扰素-γ（IFN-γ）或它们的组合刺激的小胶质细胞培养物中，15 d-PGJ（2）减少一氧化氮（NO）的产生和诱导型NO合酶（iNOS）的表达。抑制作用是剂量依赖性的，不涉及环AMP的升高，已知抑制小胶质细胞中的NOS表达的第二信使。此外，15 d-PGJ（2）下调其他小胶质细胞功能，如肿瘤坏死因子-α（TNF-α）的合成和主要组织相容性复合物II类（MHC II类）的表达。15 d-PGJ（2）的作用至少部分是通过抑制两种重要的转录因子，即信号转导和转录激活因子1和核因子κ B，已知它们介导IFN-γ和LPS细胞信号传导。我们的观察结果表明，15 d-PGJ（2），其合成可能发生在大脑中，可以在预防与过度小胶质细胞激活相关的脑损伤方面发挥重要作用。
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.