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The Journal of Neuroscience, December 1, 2000, 20(23):8637-8642

Induction of Interleukin-6 by Depolarization of Neurons

Svea Sallmann¹, Eric Jüttler¹, Simone Prinz¹, Nicole Petersen¹, Udo Knopf², Thomas Weiser³, and Markus Schwaninger¹

¹ Department of Neurology, University of Heidelberg, 69120 Heidelberg, Germany, ² Zentralinstitut für Seelische Gesundheit, 68159 Mannheim, Germany, and ³ Boehringer Ingelheim Pharma KG, 55126 Ingelheim, Germany

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.

Key words: IL-6; membrane depolarization; gene transcription; neurons; cytokine; calcium

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20238637-06$05.00/0

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