Induction of Interleukin-6 by Depolarization of Neurons
Induction of Interleukin-6 by Depolarization of Neurons
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DOI：
10.1523/jneurosci.20-23-08637.2000
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发表时间：
2000-12
期刊：
影响因子：
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通讯作者：
Svea Sallmann;E. Jüttler;Simone Prinz;N. Petersen;U. Knopf;T. Weiser;M. Schwaninger
中科院分区：
文献类型：
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作者：
Svea Sallmann;E. Jüttler;Simone Prinz;N. Petersen;U. Knopf;T. Weiser;M. Schwaninger
白细胞介素-6 （IL-6）在体内具有神经调节和神经保护作用。它在生理条件下和各种神经系统疾病中均在神经胶质细胞和神经元中表达。尽管人们对IL-6在神经胶质细胞中的表达进行了深入的研究，但对神经元对IL-6产生的调控却知之甚少。因此，我们研究了IL-6在神经元中的表达调控。细胞膜去极化增加了原代皮质细胞和PC-12细胞系中IL-6 mRNA的积累。在体内，癫痫发作后脑内IL-6 mRNA显著升高。为了研究IL-6基因的转录，将含有人IL-6启动子的报告基因构建物转染PC-12细胞。膜去极化使IL-6转录率提高了两到四倍。这种增加可以通过降低细胞外Ca2+水平或通过抑制l型Ca2+通道或Ca2+/钙调素依赖性蛋白激酶来阻止。IL-6启动子的各种元件的内部突变表明糖皮质激素反应元件（GRE） 2是一个去极化响应元件。虽然GRE2结合糖皮质激素受体（GR）并受到地塞米松的刺激，但GR并不负责膜去极化的作用，因为普遍认为GRE不介导膜去极化的刺激。相反，与IL-6 GRE2结合的另一个尚未定义的因子可能介导对膜去极化的反应。这些数据表明，神经元中IL-6的表达受到膜去极化的调节，并提出了一种新的Ca2+响应启动子元件。通过这一机制，IL-6可能作为神经元活动诱导的神经调节剂发挥作用。
Interleukin-6 (IL-6) has neuromodulatory and neuroprotective effects in vivo. It is expressed in glial cells and neurons both under physiological conditions and in various neurological diseases. Although the expression of IL-6 in glia has been intensely investigated, little is known about the regulation of IL-6 production by neurons. Therefore, we investigated the regulation of IL-6 expression in neurons. Membrane depolarization raised IL-6 mRNA accumulation in primary cortical cells and the PC-12 cell line.In vivo, IL-6 mRNA in the brain increased significantly after epileptic seizures. To investigate IL-6 gene transcription, PC-12 cells were transfected with reporter gene constructs containing the human IL-6 promoter. Membrane depolarization raised IL-6 transcription twofold to fourfold. This increase could be blocked by lowering extracellular Ca2+ levels or by inhibiting L-type Ca2+ channels or Ca2+/calmodulin-dependent protein kinases. Internal mutations in various elements of the IL-6 promoter revealed the glucocorticoid response element (GRE) 2 to be a depolarization-responsive element. Although the GRE2 bound the glucocorticoid receptor (GR) and was stimulated by dexamethasone, the GR was not responsible for the effect of membrane depolarization because a consensus GRE did not mediate stimulation by membrane depolarization. Instead, another yet undefined factor that binds to the IL-6 GRE2 may mediate the response to membrane depolarization. These data demonstrate that the expression of IL-6 in neurons is regulated by membrane depolarization and suggest a novel Ca2+-responsive promoter element. Through this mechanism, IL-6 may function as a neuromodulator induced by neuronal activity.