Abstract
ObjectiveDecreased expression of inwardly rectifying potassium (Kir) channels in astrocytes and glioma cells may contribute to impaired K+ buffering and increased propensity for seizures. Here, we evaluated the potential effect of inflammatory molecules, such as interleukin-1β (IL-1β) on Kir4.1 mRNA and protein expression.MethodsWe investigated Kir4.1 (Kcnj10) and IL-1β mRNA expression in the temporal cortex in a rat model of temporal lobe epilepsy 24 h and 1 week after induction of status epilepticus (SE), using real-time PCR and western blot analysis. The U373 glioblastoma cell line and human fetal astrocytes were used to study the regulation of Kir4.1 expression in response to pro-inflammatory cytokines. Expression of Kir4.1 protein was also evaluated by means of immunohistochemistry in surgical specimens of patients with astrocytic tumors (n = 64), comparing the expression in tumor patients with (n = 38) and without epilepsy (n = 26).ResultsTwenty-four hours after onset of SE, Kir4.1 mRNA and protein were significantly down-regulated in temporal cortex of epileptic rats. This decrease in expression was followed by a return to control level at 1 week after SE. The transient downregulation of Kir4.1 corresponded to the time of prominent upregulation of IL-1β mRNA. Expression of Kir4.1 mRNA and protein in glial cells in culture was downregulated after exposure to IL-1β. Evaluation of Kir4.1 in tumor specimens showed a significantly lower Kir4.1 expression in the specimens of patients with epilepsy compared to patients without epilepsy. This paralleled the increased presence of activated microglial cells, as well as the increased expression of IL-1β and the cytoplasmic translocation of high mobility group box 1 (HMGB1).ConclusionsTaken together, these findings indicate that alterations in expression of Kir4.1 occurring in epilepsy-associated lesions are possibly influenced by the local inflammatory environment and in particular by the inflammatory cytokine IL-1β.
Highlights
Astrocytes, the major glial cell type of the central nervous system (CNS), are known to play a major role in normal brain signaling and their dysfunction has been shown to be critically involved in the pathogenesis of several human CNS disorders, including epilepsy
Kir4.1 and IL-1β expression in rat temporal cortex after induction of status epilepticus (SE) To determine the temporal-spatial expression of Kir4.1 expression we performed quantitative PCR analysis (qPCR) in tissue samples of control rats and rats that were sacrificed at different time points after SE (1 day and 1 week post SE)
The transient prominent decrease of Kir4.1 mRNA expression following SE prompted us to evaluate whether this decrease might be related to an increased level of cytokines, such as IL-1β
Summary
Astrocytes, the major glial cell type of the central nervous system (CNS), are known to play a major role in normal brain signaling and their dysfunction has been shown to be critically involved in the pathogenesis of several human CNS disorders, including epilepsy (for reviews see [1,2]). Attention has been focused on the role of Kir channels as critical regulators of cell division, suggesting that a loss of functional Kir4.1 may underlie the re-entry of glial cells into the cell cycle supporting gliosis and tumor development [9]. These observations support an important role for astrocytic Kir4.1, it remains still unclear whether the changes in Kir4.1 expression represent the cause or the consequence of epilepsy and the mechanism underlying the regulation of the expression of Kir4.1 is still matter of discussion. Increasing evidence supports the notion that dysregulation of the astrocyte immune-inflammatory function is a common factor predisposing or directly contributing to the generation of seizures in epilepsy of various etiologies [1,22,23]
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