Induction of nerve growth factor synthesis by sphingomyelinase and ceramide in primary astrocyte cultures
Induction of nerve growth factor synthesis by sphingomyelinase and ceramide in primary astrocyte cultures
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DOI：
10.1016/s0169-328x(97)00230-1
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发表时间：
1997-12-01
期刊：
影响因子：
--
通讯作者：
DiazLaviada, I
中科院分区：
文献类型：
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作者：
GalveRoperh, I;Haro, A;DiazLaviada, I
星形胶质细胞响应促炎细胞因子合成神经生长因子（NGF）。为了进一步研究诱导 NGF 产生的信号传导机制，对鞘磷脂 (SM) 途径进行了研究。在新生大鼠皮质星形胶质细胞的原代培养物中添加外源性中性 SMase（金黄色葡萄球菌）或 C-2-神经酰胺可引起 NGF 合成的剂量反应增加，分别在 1 U/ml 和 25 muM 时达到最大效果。 SMase 和神经酰胺诱导 NGF 合成与经典 PKC 活性无关。细胞内 cAMP 升高剂，例如毛喉素和 3-异丁基-1-甲基黄嘌呤，部分阻止 SMase 和 C-2-神经酰胺诱导的 NGF 分泌到细胞上清液中。 PD098059 和芹菜素是丝裂原激活蛋白 (MAP) 激酶途径的抑制剂，对 SMase 和 C-2-cer 诱导的 NGF 释放产生剂量反应抑制。这一观察结果表明，SMase 途径对 NGF 合成和分泌的调节可能是由 MAP 激酶级联下游介导的。事实上，用 SMase 或 C-8-神经酰胺预处理星形胶质细胞会导致 raf-1 磷酸化增加。此外，用 SMase 或两种神经酰胺处理的星形胶质细胞中 MAP 激酶活性增强。总之，结果表明 SMase 途径可能控制中枢神经系统中的 NGF 合成，并增加了 MAP 激酶级联参与该过程的可能性。 (C) 1997 Elsevier Science B.V.
Astrocytes synthesize nerve growth factor (NGF) in response to pro-inflammatory cytokines. To further study the signaling mechanism involved in this induction of NGF production, the sphingomyelin (SM) pathway was studied. Addition of exogenous neutral SMase (Staphylococcus aureus) or C-2-ceramide to primary cultures of newborn rat cortical astrocytes elicited a dose-response increase of NGF synthesis, with maximal effect at 1 U/ml and 25 mu M, respectively. Induction of NGF synthesis by SMase and ceramide was shown to be independent of classical PKC activity. Intracellular cAMP-raising agents, such as forskolin and 3-isobutyl-1-methylxanthine, partially prevented the SMase- and C-2-ceramide-induced secretion of NGF to the cell supernatant. PD098059 and apigenin, inhibitors of the mitogen-activated protein (MAP) kinase pathway, produced a dose-response inhibition of the SMase- and C-2-cer-induced release of NGF. This observation points to the possibility that regulation of NGF synthesis and secretion by the SMase pathway may be mediated downstream by the MAP kinase cascade. As a matter of fact, pre-treatment of astrocytes with SMase or C-8-ceramide led to an increased phosphorylation of raf-1. Moreover, MAP kinase activity was enhanced in astrocytes treated with SMase or both ceramides. In conclusion, results suggest that the SMase pathway may control NGF synthesis in the central nervous system, and raise the possibility of an involvement of the MAP kinase cascade in this process. (C) 1997 Elsevier Science B.V.