Sallmann S, Jüttler E, Prinz S, Petersen N, Knopf U, Weiser T, Schwaninger M
Department of Neurology, University of Heidelberg, 69120 Heidelberg, Germany.
J Neurosci. 2000 Dec 1;20(23):8637-42. doi: 10.1523/JNEUROSCI.20-23-08637.2000.
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 Ca(2+) levels or by inhibiting L-type Ca(2+) channels or Ca(2+)/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 Ca(2+)-responsive promoter element. Through this mechanism, IL-6 may function as a neuromodulator induced by neuronal activity.
白细胞介素-6（IL-6）在体内具有神经调节和神经保护作用。它在生理条件下以及各种神经疾病中，均在神经胶质细胞和神经元中表达。尽管对神经胶质细胞中IL-6的表达已进行了深入研究，但关于神经元对IL-6产生的调节却知之甚少。因此，我们研究了神经元中IL-6表达的调节机制。膜去极化可提高原代皮质细胞和PC-12细胞系中IL-6 mRNA的积累。在体内，癫痫发作后大脑中的IL-6 mRNA显著增加。为了研究IL-6基因转录，用含有人类IL-6启动子的报告基因构建体转染PC-12细胞。膜去极化使IL-6转录增加了两倍至四倍。这种增加可通过降低细胞外Ca(2+)水平、抑制L型Ca(2+)通道或Ca(2+)/钙调蛋白依赖性蛋白激酶来阻断。IL-6启动子各种元件的内部突变显示糖皮质激素反应元件（GRE）2是一个去极化反应元件。尽管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，因为一个共有GRE并不能介导膜去极化的刺激。相反，另一种尚未明确的与IL-6 GRE2结合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的表达受膜去极化调节，并提示存在一种新的Ca(2+)反应性启动子元件。通过这种机制，IL-6可能作为一种由神经元活动诱导的神经调节剂发挥作用。
