Induction of interleukin-6 by depolarization of neurons

Interleukin-6 (IL-6) has neuromodulatory and neuroprotective effects in viv o. It is expressed in glial cells and neurons both under physiological cond itions and in various neurological diseases. Although the expression of IL- 6 in glia has been intensely investigated, little is known about the regula tion of IL-6 production by neurons. Therefore, we investigated the regulati on 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 i nvestigate IL-6 gene transcription, PC-12 cells were transfected with repor ter gene constructs containing the human IL-6 promoter. Membrane depolariza tion raised IL-6 transcription twofold to fourfold. This increase could be blocked by lowering extracellular Ca2+ levels or by inhibiting L-type Ca2channels or Ca2+/calmodulin-dependent protein kinases. Internal mutations i n various elements of the IL-6 promoter revealed the glucocorticoid respons e element (GRE) 2 to be a depolarization-responsive element. Although the G RE2 bound the glucocorticoid receptor (GR) and was stimulated by dexamethas one, the GR was not responsible for the effect of membrane depolarization b ecause a consensus GRE did not mediate stimulation by membrane depolarizati on. Instead, another yet undefined factor that binds to the IL-6 GRE2 may m ediate 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 mechanis m, IL-6 may function as a neuromodulator induced by neuronal activity.