15-Deoxy-Δ12,14-prostaglandin J2 regulates the functional state and the survival of microglial cells through multiple molecular mechanisms
15-Deoxy-Δ12,14-prostaglandin J2 regulates the functional state and the survival of microglial cells through multiple molecular mechanisms
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DOI：
10.1046/j.1471-4159.2003.02045.x
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发表时间：
2003-11-01
影响因子：
4.7
通讯作者：
Minghetti, L
中科院分区：
文献类型：
--
作者：
Bernardo, A;Ajmone-Cat, MA;Minghetti, L
我们之前报道过，大鼠原代小胶质细胞培养物表达核受体过氧化物酶体增殖激活受体- γ (ppar - γ)，并且与这些细胞激活相关的几种功能，包括一氧化氮（NO）和肿瘤坏死因子- α合成，被15-脱氧- δ(12,14)-前列腺素J(2) （15d-PGJ(2)）和西格列酮（两种特异性ppar - γ激动剂）下调。本研究表明，小胶质细胞不仅表达具有功能活性的ppar - γ，而且在脂多糖（LPS）刺激下还能合成大量的15d-PGJ(2)。此外，我们发现，虽然15d-PGJ(2)和西格列酮在1-5 μ m浓度下对减少小胶质细胞的激活同样有效，但15d-PGJ(2)在低浓度（0.1 μ m）下减少了PGE(2)的产生，并在高浓度（10 μ m）下诱导了时间依赖性的小胶质细胞损伤和凋亡，而西格列酮则没有。有趣的是，抑制PGE(2)的产生主要是通过抑制环氧化酶-2的酶活性来实现的，因为这种酶和PGE合成酶的微粒体异构体的表达保持不变。这些发现表明，15d-PGJ(2)通过部分依赖ppar - γ的机制影响激活的小胶质细胞的功能状态和存活，15d-PGJ(2)的浓度在决定受影响的特定小胶质细胞功能方面至关重要。
We have previously reported that rat primary microglial cultures express the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and that several functions associated with the activation of these cells, including nitric oxide (NO) and tumor necrosis factor-alpha synthesis, are down-regulated by 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and ciglitazone, two specific PPAR-gamma agonists. Here we demonstrate that microglial cells not only express a functionally active PPAR-gamma, but also synthesize large amounts of 15d-PGJ(2) upon stimulation with lipopolysaccharide (LPS). In addition, we show that, although 15d-PGJ(2) and ciglitazone were equally effective in reducing microglial activation when used at 1-5 mum concentrations, 15d-PGJ(2), but not of ciglitazone, reduced PGE(2) production at low concentration (0.1 mum) and induced a time-dependent microglial impairment and apoptosis at high concentration (10 mum). Interestingly, the inhibition of PGE(2) production was achieved mainly through the inhibition of cycloxygenase-2 enzymatic activity, as the expression of this enzyme and that of the microsomal isoform of PGE synthase remained unaltered. These findings suggest that 15d-PGJ(2) affects the functional state and the survival of activated microglia through mechanisms only in part dependent on PPAR-gamma and that the concentration of 15d-PGJ(2) is crucial in determining the particular microglial function affected.