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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2012

Open Access 01-12-2012 | Research

Regulation of Kir4.1 expression in astrocytes and astrocytic tumors: a role for interleukin-1 β

Authors: Emanuele Zurolo, Marjolein de Groot, Anand Iyer, Jasper Anink, Erwin A van Vliet, Jan J Heimans, Jaap C Reijneveld, Jan A Gorter, Eleonora Aronica

Published in: Journal of Neuroinflammation | Issue 1/2012

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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.
Literature
1.
Aronica E, Ravizza T, Zurolo E, Vezzani A: Astrocyte immune responses in epilepsy. Glia 2012, 60:1258–1268.CrossRefPubMed
2.
Steinhauser C, Seifert G: Astrocyte dysfunction in epilepsy. In Jasper’s Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Edited by: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV. Bethesda (MD): National Center for Biotechnology Information (US); 2012.
3.
Steinhauser C, Seifert G: Glial membrane channels and receptors in epilepsy: impact for generation and spread of seizure activity. Eur J Pharmacol 2002, 447:227–237.CrossRefPubMed
4.
Seifert G, Carmignoto G, Steinhauser C: Astrocyte dysfunction in epilepsy. Brain Res Rev 2010, 63:212–221.CrossRefPubMed
5.
Djukic B, Casper KB, Philpot BD, Chin LS, McCarthy KD: Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation. J Neurosci 2007, 27:11354–11365.CrossRefPubMed
6.
Chever O, Djukic B, McCarthy KD, Amzica F: Implication of Kir4.1 channel in excess potassium clearance: an in vivo study on anesthetized glial-conditional Kir4.1 knock-out mice. J Neurosci 2010, 30:15769–15777.CrossRefPubMed
7.
Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, Tobin J, Lieberer E, Sterner C, Landoure G, Arora R, Sirimanna T, Thompson D, Cross JH, van’t Hoff W, Al Masri O, Tullus K, Yeung S, Anikster Y, Klootwijk E, Hubank M, Dillon MJ, Heitzmann D, Arcos-Burgos M, Knepper MA, Dobbie A, Gahl WA, Warth R, Sheridan E, Kleta R: Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Eng J Med 2009, 360:1960–1970.CrossRef
8.
Haj-Yasein NN, Jensen V, Vindedal GF, Gundersen GA, Klungland A, Ottersen OP, Hvalby O, Nagelhus EA: Evidence that compromised K + spatial buffering contributes to the epileptogenic effect of mutations in the human Kir4.1 gene (KCNJ10). Glia 2011, 59:1635–1642.CrossRefPubMed
9.
Olsen ML, Sontheimer H: Functional implications for Kir4.1 channels in glial biology: from K + buffering to cell differentiation. J Neurochem 2008, 107:589–601.CrossRefPubMedPubMedCentral
10.
Schroder W, Hinterkeuser S, Seifert G, Schramm J, Jabs R, Wilkin GP, Steinhauser C: Functional and molecular properties of human astrocytes in acute hippocampal slices obtained from patients with temporal lobe epilepsy. Epilepsia 2000, Suppl 6:S181-S184.CrossRef
11.
Jauch R, Windmuller O, Lehmann TN, Heinemann U, Gabriel S: Effects of barium, furosemide, ouabaine and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) on ionophoretically-induced changes in extracellular potassium concentration in hippocampal slices from rats and from patients with epilepsy. Brain Res 2002, 925:18–27.CrossRefPubMed
12.
Heinemann U, Gabriel S, Jauch R, Schulze K, Kivi A, Eilers A, Kovacs R, Lehmann TN: Alterations of glial cell function in temporal lobe epilepsy. Epilepsia 2000, Suppl 6:S185-S189.CrossRef
13.
Kivi A, Lehmann TN, Kovacs R, Eilers A, Jauch R, Meencke HJ, von Deimling A, Heinemann U, Gabriel S: Effects of barium on stimulus-induced rises of [K+]o in human epileptic non-sclerotic and sclerotic hippocampal area CA1. Eur J Neurosci 2000, 12:2039–2048.CrossRefPubMed
14.
Bordey A, Sontheimer H: Electrophysiological properties of human astrocytic tumor cells In situ: enigma of spiking glial cells. J Neurophysiol 1998, 79:2782–2793.PubMed
15.
Stewart TH, Eastman CL, Groblewski PA, Fender JS, Verley DR, Cook DG, D’Ambrosio R: Chronic dysfunction of astrocytic inwardly rectifying K + channels specific to the neocortical epileptic focus after fluid percussion injury in the rat. J Neurophysiol 2010, 104:3345–3360.CrossRefPubMedPubMedCentral
16.
Warth A, Mittelbronn M, Wolburg H: Redistribution of the water channel protein aquaporin-4 and the K + channel protein Kir4.1 differs in low- and high-grade human brain tumors. Acta Neuropathol 2005, 109:418–426.CrossRefPubMed
17.
Tan G, Sun SQ, Yuan DL: Expression of Kir 4.1 in human astrocytic tumors: correlation with pathologic grade. Biochem Biophys Res Commun 2008, 367:743–747.CrossRefPubMed
18.
19.
Ivens S, Kaufer D, Flores LP, Bechmann I, Zumsteg D, Tomkins O, Seiffert E, Heinemann U, Friedman A: TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 2007, 130:535–547.CrossRefPubMed
20.
Olsen ML, Campbell SC, McFerrin MB, Floyd CL, Sontheimer H: Spinal cord injury causes a wide-spread, persistent loss of Kir4.1 and glutamate transporter 1: benefit of 17 beta-oestradiol treatment. Brain 2010, 133:1013–1025.CrossRefPubMedPubMedCentral
21.
Zhang Y, Xu G, Ling Q, Da C: Expression of aquaporin 4 and Kir4.1 in diabetic rat retina: treatment with minocycline. J Int Med Res 2011, 39:464–479.CrossRefPubMed
22.
Vezzani A, Maroso M, Balosso S, Sanchez MA, Bartfai T: IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain Behav Immun 2011, 25:1281–1289.CrossRefPubMed
23.
Aronica E, Crino PB: Inflammation in epilepsy: clinical observations. Epilepsia 2011, Suppl 3:26–32.CrossRef
24.
Kim JE, Choi HC, Song HK, Jo SM, Kim DS, Choi SY, Kim YI, Kang TC: Levetiracetam inhibits interleukin-1 beta inflammatory responses in the hippocampus and piriform cortex of epileptic rats. Neurosci Lett 2010, 471:94–99.CrossRefPubMed
25.
Stienen MN, Haghikia A, Dambach H, Thone J, Wiemann M, Gold R, Chan A, Dermietzel R, Faustmann PM, Hinkerohe D, Prochnow N: Anti-inflammatory effects of the anticonvulsant drug levetiracetam on electrophysiological properties of astroglia are mediated via TGFbeta1 regulation. Br J Neuropharm 2011, 162:491–507.CrossRef
26.
Gorter JA, van Vliet EA, Aronica E, da Silva FHL: Progression of spontaneous seizures after status epilepticus is related with extensive bilateral loss of hilar parvalbumin and somatostatin immunoreactive neurons. Eur J Neurosci 2001, 13:657–669.CrossRefPubMed
27.
Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ, Klenk DC: Measurement of protein using bicinchoninic acid [published erratum appears in Anal Biochem 1987 May 15;163(1):279]. Anal Biochem 1985, 150:76–85.CrossRefPubMed
28.
Aronica E, Gorter JA, Ijlst-Keizers H, Rozemuller AJ, Yankaya B, Leenstra S, Troost D: Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Eur J Neurosci 2003, 17:2106–2118.CrossRefPubMed
29.
Aronica E, Gorter JA, Rozemuller AJ, Yankaya B, Troost D: Interleukin-1 beta down-regulates the expression of metabotropic glutamate receptor 5 in cultured human astrocytes. J Neuroimmunol 2005, 160:188–194.CrossRefPubMed
30.
Aronica E, Gorter JA, Redeker S, van Vliet EA, Ramkema M, Scheffer GL, Scheper RJ, van der Valk P, Leenstra S, Baayen JC, Spliet WG, Troost D: Localization of breast cancer resistance protein (BCRP) in microvessel endothelium of human control and epileptic brain. Epilepsia 2005, 46:849–857.CrossRefPubMed
31.
Ramakers C, Ruijter JM, Deprez RH, Moorman AF: Assumption-free analysis of quantitative real-time polymerase chain reaction (PCR) data. Neurosci Lett 2003, 339:62–66.CrossRefPubMed
32.
Louis DN, Ohgaki H, Wiestler OD, Cavanee WK: WHO Classification of Tumours of the Central Nervous System . Lyon: IARC; 2007.
33.
Ravizza T, Boer K, Redeker S, Spliet WGM, van Rijen PC, Troost D, Vezzani A, Aronica E: The IL-1 system in epilepsy-associated malformations of cortical development. Neurobiol Dis 2006, 24:128–143.CrossRefPubMed
34.
Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer AM, Rossetti C, Molteni M, Manfredi AA, Bianchi ME, Vezzani A: Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med 2010, 16:413–419.CrossRefPubMed
35.
de Groot M, Reijneveld JC, Aronica E, Heimans JJ: Epilepsy in patients with a brain tumour: focal epilepsy requires focused treatment. Brain 2012, 135:1002–1016.CrossRefPubMed
36.
Aronica E, Gorter JA, Redeker S, Ramkema M, Spliet WG, van Rijen PC, Leenstra S, Troost D: Distribution, characterization and clinical significance of microglia in glioneuronal tumours from patients with chronic intractable epilepsy. Neuropathol Appl Neurobiol 2005, 31:280–291.CrossRefPubMed
37.
de Groot M, Iyer A, Zurolo E, Anink J, Heimans JJ, Boison D, Reijneveld JC, Aronica E: Overexpression of ADK in human astrocytic tumors and peritumoral tissue is related to tumor-associated epilepsy. Epilepsia 2012, 53:58–66.CrossRefPubMed
38.
Dinarello CA: Biologic basis for interleukin-1 in disease. Blood 1996, 87:2095–2147.PubMed
39.
Andersson A, Covacu R, Sunnemark D, Danilov AI, Dal Bianco A, Khademi M, Wallstrom E, Lobell A, Brundin L, Lassmann H, Harris RA: Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis. J Leukoc Biol 2008, 84:1248–1255.CrossRefPubMed
40.
Hreggvidsdottir HS, Ostberg T, Wahamaa H, Schierbeck H, Aveberger AC, Klevenvall L, Palmblad K, Ottosson L, Andersson U, Harris HE: The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation. J Leukoc Biol 2009, 86:655–662.CrossRefPubMed
41.
42.
Gorter JA, Van Vliet E, Aronica E, Rauwerda H, Breit T, Lopes da Silva FH, Wadman WJ: Potential new antiepileptogenic targets indicated by microarray analysis in a rat model for temporal lobe epilepsy. J Neurosci 2006, 26:11083–11110.CrossRefPubMed
43.
De Simoni MG, Perego C, Ravizza T, Moneta D, Conti M, Marchesi F, De Luigi A, Garattini S, Vezzani A: Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur J Neurosci 2000, 12:2623–2633.CrossRefPubMed
44.
Patel HC, Boutin H, Allan SM: Interleukin-1 in the brain: mechanisms of action in acute neurodegeneration. Ann N Y Acad Sci 2003, 992:39–47.CrossRefPubMed
45.
Rothwell N: Interleukin-1 and neuronal injury: mechanisms, modification, and therapeutic potential. Brain Behav Immun 2003, 17:152–157.CrossRefPubMed
46.
Gibson RM, Rothwell NJ, Le Feuvre RA: CNS injury: the role of the cytokine IL-1. Vet J 2004, 168:230–237.CrossRefPubMed
47.
Pannicke T, Uckermann O, Iandiev I, Wiedemann P, Reichenbach A, Bringmann A: Ocular inflammation alters swelling and membrane characteristics of rat Muller glial cells. J Neuroimmunol 2005, 161:145–154.CrossRefPubMed
48.
Reichenbach A, Wurm A, Pannicke T, Iandiev I, Wiedemann P, Bringmann A: Muller cells as players in retinal degeneration and edema. Graefes Arch Clin Exp Ophthalmol 2007, 245:627–636.CrossRefPubMed
49.
Kaiser M, Maletzki I, Hulsmann S, Holtmann B, Schulz-Schaeffer W, Kirchhoff F, Bahr M, Neusch C: Progressive loss of a glial potassium channel (KCNJ10) in the spinal cord of the SOD1 (G93A) transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem 2006, 99:900–912.CrossRefPubMed
50.
Lucas SM, Rothwell NJ, Gibson RM: The role of inflammation in CNS injury and disease. Br J Pharmacol 2006, Suppl 1:S232-S240.
51.
Zhang Z, Zhang ZY, Fauser U, Schluesener HJ: Valproic acid attenuates inflammation in experimental autoimmune neuritis. Cell Mol Life Sci. 2008, 65:4055–4065.CrossRefPubMed
52.
Giometto B, Bozza F, Faresin F, Alessio L, Mingrino S, Tavolato B: Immune infiltrates and cytokines in gliomas. Acta Neuroch 1996, 138:50–56.CrossRef
53.
Ishii N, Tada M, Sakuma S, Sawamura Y, Shinohe Y, Abe H: Human astrocytoma cells are capable of producing macrophage inflammatory protein-1beta. J Neurooncol 1998, 37:17–23.CrossRefPubMed
54.
Sasaki A, Tamura M, Hasegawa M, Ishiuchi S, Hirato J, Nakazato Y: Expression of interleukin-1beta mRNA and protein in human gliomas assessed by RT-PCR and immunohistochemistry. J Neuropathol Exp Neurol 1998, 57:653–663.CrossRefPubMed
55.
Sharma V, Dixit D, Koul N, Mehta VS, Sen E: Ras regulates interleukin-1beta-induced HIF-1alpha transcriptional activity in glioblastoma. J Mol Med 2011, 89:123–136.CrossRefPubMed
56.
Iwami K, Natsume A, Wakabayashi T: Cytokine networks in glioma. Neurosurg Rev 2011, 34:253–263. discussion 263–254.CrossRefPubMed
57.
Vezzani A, Ravizza T, Balosso S, Aronica E: Glia as a source of cytokines: implications for neuronal excitability and survival. Epilepsia 2008, 49:24–32.CrossRefPubMed
58.
Ye ZC, Sontheimer H: Glioma cells release excitotoxic concentrations of glutamate. Cancer Res 1999, 59:4383–4391.PubMed
59.
Hu S, Sheng WS, Ehrlich LC, Peterson PK, Chao CC: Cytokine effects on glutamate uptake by human astrocytes. Neuroimmunomodulation 2000, 7:153–159.CrossRefPubMed
60.
Casamenti F, Prosperi C, Scali C, Giovannelli L, Colivicchi MA, Faussone-Pellegrini MS, Pepeu G: Interleukin-1beta activates forebrain glial cells and increases nitric oxide production and cortical glutamate and GABA release in vivo: implications for Alzheimer’s disease. Neuroscience 1999, 91:831–842.CrossRefPubMed
61.
Vezzani A, Aronica E, Mazarati A, Pittman QJ: Epilepsy and brain inflammation. Exp Neurol 2011. [Epub ahead of print].
62.
Hayakawa K, Arai K, Lo EH: Role of ERK map kinase and CRM1 in IL-1beta-stimulated release of HMGB1 from cortical astrocytes. Glia 2010, 58:1007–1015.PubMed
63.
Zurolo E, Iyer A, Maroso M, Carbonell C, Anink JJ, Ravizza T, Fluiter K, Spliet WG, van Rijen PC, Vezzani A, Aronica E: Activation of Toll-like receptor, RAGE and HMGB1 signalling in malformations of cortical development. Brain 2011, 134:1015–1032.CrossRefPubMed
64.
Bassi R, Giussani P, Anelli V, Colleoni T, Pedrazzi M, Patrone M, Viani P, Sparatore B, Melloni E, Riboni L: HMGB1 as an autocrine stimulus in human T98G glioblastoma cells: role in cell growth and migration. J Neurooncol 2008, 87:23–33.CrossRefPubMed
65.
Thom M, Blumcke I, Aronica E: Long-term epilepsy-associated tumors. Brain Pathol 2012, 22:350–379.CrossRefPubMed
66.
Wilcock DM, Vitek MP, Colton CA: Vascular amyloid alters astrocytic water and potassium channels in mouse models and humans with Alzheimer’s disease. Neuroscience 2009, 159:1055–1069.CrossRefPubMedPubMedCentral
67.
Srivastava R, Aslam M, Kalluri SR, Schirmer L, Buck D, Tackenberg B, Rothhammer V, Chan A, Gold R, Berthele A, Bennett JL, Korn T, Hemmer B: Potassium channel KIR4.1 as an immune target in multiple sclerosis. N Engl J Med 2012, 367:115–123.CrossRefPubMed
Metadata
Title
Regulation of Kir4.1 expression in astrocytes and astrocytic tumors: a role for interleukin-1 β
Authors
Emanuele Zurolo
Marjolein de Groot
Anand Iyer
Jasper Anink
Erwin A van Vliet
Jan J Heimans
Jaap C Reijneveld
Jan A Gorter
Eleonora Aronica
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-9-280

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