title: Regulation of Kir4.1 expression in astrocytes and astrocytic tumors: a role for interleukin-1 β.
abstract: OBJECTIVE
  Decreased 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.
  
  
  METHODS
  We 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).
  
  
  RESULTS
  Twenty-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).
  
  
  CONCLUSIONS
  Taken 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.
authors.affiliation: Department of Neuro-Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam AZ 1105, The Netherlands.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Zurolo
authors.forename: Marjolein
authors.initials: M
authors.lastname: de Groot
authors.forename: Anand
authors.initials: A
authors.lastname: Iyer
authors.forename: Jasper
authors.initials: J
authors.lastname: Anink
authors.forename: Erwin A
authors.initials: EA
authors.lastname: van Vliet
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Heimans
authors.forename: Jaap C
authors.initials: JC
authors.lastname: Reijneveld
authors.forename: Jan A
authors.initials: JA
authors.lastname: Gorter
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004833:Epilepsy, Temporal Lobe / Q000473:pathology; D005333:Fetus; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013702:Temporal Lobe / Q000473:pathology; D000098854:Kcnj10 Channel
chemical_list: D024243:HMGB1 Protein; D053583:Interleukin-1beta; D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger