Induction of Interleukin-6 by Depolarization of Neurons

Abstract

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.

Differential Implication of Proinflammatory Cytokine Interleukin-6 in the Development of Cephalic versus Extracephalic Neuropathic Pain in Rats

“…In contrast, SN-CCI-induced upregulation of IL-6 mRNA in DRG peaked only 1 week after surgery. Such a rapid induction of IL-6 mRNA levels in TG of IoN-CCI rats could suggest an activitydependent induction (Sallmann et al, 2000), in opposition to the slower induction observed in the DRGs of SN-CCI rats, which would require retrograde signals (Murphy et al, 1999). Altogether, these data suggest a different response of sensory ganglia cells to injury in IoN-CCI versus SN-CCI rats.…”

DNA microarray analysis of the contused spinal cord: Effect of NMDA receptor inhibition

“…Sallmann et al (2000) also found that depolarization-induced IL-6 transcription depends on calcium and calcium calmodulin-dependent kinases, suggesting that NMDA receptor activation may contribute to IL-6 mRNA increases after SCI. Figure 5D also shows that (NR1 staining increases 12 hours after injury.…”

“…Interleukin-1, TNFs, and depolarization have all been reported to stimulate IL-6 expression in cortical and sensory neurons (Ringheim et al, 1995;Sallmann et al, 2000). Sallmann et al (2000) also found that depolarization-induced IL-6 transcription depends on calcium and calcium calmodulin-dependent kinases, suggesting that NMDA receptor activation may contribute to IL-6 mRNA increases after SCI.…”

Ambivalent Aspects of Interleukin-6 in Cerebral Ischemia: Inflammatory versus Neurotrophic Aspects

“…Sallmann et al (2000) investigated the regulation of IL-6 expression in the PC-12 cell line. They clearly showed that neuronal IL-6 expression is regulated by membrane depolarization and inhibited by decreased extracellular Ca 2 + levels.…”