TY - JOUR T1 - Induction of Interleukin-6 by Depolarization of Neurons JF - The Journal of Neuroscience JO - J. Neurosci. SP - 8637 LP - 8642 DO - 10.1523/JNEUROSCI.20-23-08637.2000 VL - 20 IS - 23 AU - Svea Sallmann AU - Eric Jüttler AU - Simone Prinz AU - Nicole Petersen AU - Udo Knopf AU - Thomas Weiser AU - Markus Schwaninger Y1 - 2000/12/01 UR - http://www.jneurosci.org/content/20/23/8637.abstract N2 - 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. ER -