Schneider N, Lanz S, Ramer R, Schaefer D, Goppelt-Struebe M
Medizinische Klinik IV, Universität Erlangen-Nürnberg, Erlangen, Germany Kompetenzzentrum Umweltmedizin, Rupprecht-Karls-Universität Heidelberg, Mannheim, Germany.
J Neurochem. 2001 Apr;77(2):416-24. doi: 10.1046/j.1471-4159.2001.00264.x.
Cyclooxygenases-1 and -2 are both expressed in neuronal cells in vivo. In the neuroblastoma cell lines NG108 and N2a, however, only cyclooxygenase-1 was detectable. Differentiation of the cells with retinoic acid increased cyclooxygenase-1 mRNA and protein expression within 24 and 48 h, respectively. A further increase was observed when the cells were concomitantly treated with the glucocorticoid dexamethasone (a 2-3-fold increase compared with retinoic acid alone). In the absence of retinoic acid, dexamethasone only slightly up-regulated cyclooxygenase-1 expression. The inhibitor of protein synthesis cycloheximide abrogated the effect of dexamethasone, indicating the involvement of newly synthesised proteins. Retinoic acid increased the transcription of cyclooxygenase-1 mRNA, determined with a luciferase-coupled promoter construct. Dexamethasone only slightly augmented cyclooxygenase-1-promoter activity but increased cyclooxygenase-1 mRNA stability. Other corticosteroids, hydrocortisone and aldosterone, also up-regulated cyclooxygenase-1 whereas neurosteroids or oestrogen were ineffective. Up-regulation was mediated primarily by the glucocorticoid receptor, because the receptor antagonist RU486 strongly reduced the effects of all corticosteroids. This indicated that in NG108 cells, the mineralocorticoid aldosterone may bind to the glucocorticoid receptor. Treatment of NG108 or N2a cells with corticosteroids did not alter the morphological phenotype obtained during differentiation. We thus show that corticosteroids, which down-regulate cyclooxygenase expression in most cell types, up-regulate cyclooxygenase-1 during neuronal differentiation.
环氧化酶-1和-2在体内的神经元细胞中均有表达。然而，在神经母细胞瘤细胞系NG108和N2a中，仅可检测到环氧化酶-1。用视黄酸诱导细胞分化，分别在24小时和48小时内增加了环氧化酶-1的mRNA和蛋白质表达。当细胞同时用糖皮质激素地塞米松处理时，观察到进一步增加（与单独使用视黄酸相比增加了2-3倍）。在没有视黄酸的情况下，地塞米松仅轻微上调环氧化酶-1的表达。蛋白质合成抑制剂环己酰亚胺消除了地塞米松的作用，表明新合成的蛋白质参与其中。用荧光素酶偶联启动子构建体测定，视黄酸增加了环氧化酶-1 mRNA的转录。地塞米松仅轻微增强环氧化酶-1启动子活性，但增加了环氧化酶-1 mRNA的稳定性。其他皮质类固醇，氢化可的松和醛固酮，也上调环氧化酶-1，而神经甾体或雌激素则无效。上调主要由糖皮质激素受体介导，因为受体拮抗剂RU486强烈降低了所有皮质类固醇的作用。这表明在NG108细胞中，盐皮质激素醛固酮可能与糖皮质激素受体结合。用皮质类固醇处理NG108或N2a细胞不会改变分化过程中获得的形态表型。因此，我们表明，在大多数细胞类型中下调环氧化酶表达的皮质类固醇在神经元分化过程中上调环氧化酶-1。
