Hippocampal gene expression dysregulation of Klotho, nuclear factor kappa B and tumor necrosis factor in temporal lobe epilepsy patients

Journal of Neuroinflammation

Lília D’Souza-Li¹  Helder Tedeschi²  Evandro Pinto da Luz de Oliveira²  Ana Érika Dias Ferreira¹  Marcelo Ananias Teocchi¹ 

[1] Laboratory of Pediatric Endocrinology, Center for Investigation in Pediatrics, University of Campinas, PO Box 6111, Campinas, SP, 13083-970, Brazil;Department of Neurology, Faculty of Medical Sciences, University of Campinas, PO Box 6111, Campinas, SP, 13083-970, Brazil

关键词: Calcium homeostasis;    Reference genes;    GFAP;    NFKB1;    KL;    TNF;    Neuroinflammation;    Hippocampal sclerosis;    Seizures;   

Others  :  1159992
DOI  :  10.1186/1742-2094-10-53

 received in 2012-11-01, accepted in 2013-03-19,  发布年份 2013

【 摘 要 】

Background

Previous research in animal seizure models indicates that the pleiotropic cytokine TNF is an important effector/mediator of neuroinflammation and cell death. Recently, it has been demonstrated that TNF downregulates Klotho (KL) through the nuclear factor kappa B (NFkB) system in animal models of chronic kidney disease and colitis. KL function in the brain is unclear, although Klotho knockout (Kl^−/−) mice exhibit neural degeneration and a reduction of hippocampal synapses. Our aim was to verify if the triad KL-NFKB1-TNF is also dysregulated in temporal lobe epilepsy associated with hippocampal sclerosis (TLE(HS)) patients.

Findings

We evaluated TNF, NFKB1 and KL relative mRNA expression levels by reverse transcription quantitative PCR (RT-qPCR) in resected hippocampal tissue samples from 14 TLE(HS) patients and compared them to five post mortem controls. Four reference genes were used: GAPDH, HPRT1, ENO2 and TBP. We found that TNF expression was dramatically upregulated in TLE(HS) patients (P <0.005). NFKB1 expression was also increased (P <0.03) while KL was significantly downregulated (P <0.03) in TLE(HS) patients. Hippocampal KL expression had an inverse correlation with NFKB1 and TNF.

Conclusions

Our data suggest that, similar to other inflammatory diseases, TNF downregulates KL through NFkB in TLE(HS) patients. The remarkable TNF upregulation in patients is a strong indication of hippocampal chronic inflammation. Our finding of hippocampal KL downregulation has wide implications not only for TLE(HS) but also for other neuronal disorders related to neurodegeneration associated with inflammation.

【 授权许可】

   
2013 Teocchi et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Semah F, Picot MC, Adam C, Broglin D, Arzimanoglou A, Bazin B, Cavalcanti D, Baulac M: Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 1998, 51:1256-1262.
• [2]Greenfield JG, Graham DI, Lantos PL: Greenfield’s Neuropathology. 6th edition. London: Arnold; 1997.
• [3]Delorenzo RJ, Sun DA, Deshpande LS: Cellular mechanisms underlying acquired epilepsy: the calcium hypothesis of the induction and maintainance of epilepsy. Pharmacol Ther 2005, 105:229-266.
• [4]Raza M, Deshpande LS, Blair RE, Carter DS, Sombati S, DeLorenzo RJ: Aging is associated with elevated intracellular calcium levels and altered calcium homeostatic mechanisms in hippocampal neurons. Neurosci Lett 2007, 418:77-81.
• [5]Huang CL, Moe OW: Klotho: a novel regulator of calcium and phosphorus homeostasis. Pflugers Arch 2011, 462:185-193.
• [6]Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI: Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997, 390:45-51.
• [7]Li SA, Watanabe M, Yamada H, Nagai A, Kinuta M, Takei K: Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct Funct 2004, 29:91-99.
• [8]de Oliveira RM: Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway. FEBS Lett 2006, 580:5753-5758.
• [9]Ravizza T, Balosso S, Vezzani A: Inflammation and prevention of epileptogenesis. Neurosci Lett 2011, 497:223-230.
• [10]Foresti ML, Arisi GM, Shapiro LA: Role of glia in epilepsy-associated neuropathology, neuroinflammation and neurogenesis. Brain Res Rev 2011, 66:115-122.
• [11]Li G, Bauer S, Nowak M, Norwood B, Tackenberg B, Rosenow F, Knake S, Oertel WH, Hamer HM: Cytokines and epilepsy. Seizure 2011, 20:249-256.
• [12]Plata-Salaman CR, Ilyin SE, Turrin NP, Gayle D, Flynn MC, Romanovitch AE, Kelly ME, Bureau Y, Anisman H, McIntyre DC: Kindling modulates the IL-1beta system, TNF-alpha, TGF-beta1, and neuropeptide mRNAs in specific brain regions. Brain Res Mol Brain Res 2000, 75:248-258.
• [13]Godlevsky LS, Shandra AA, Oleinik AA, Vastyanov RS, Kostyushov VV, Timchishin OL: TNF-alpha in cerebral cortex and cerebellum is affected by amygdalar kindling but not by stimulation of cerebellum. Pol J Pharmacol 2002, 54:655-660.
• [14]Vezzani A, Moneta D, Richichi C, Aliprandi M, Burrows SJ, Ravizza T, Perego C, De Simoni MG: Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis. Epilepsia 2002, 43(Suppl 5):30-35.
• [15]Vezzani A, Friedman A: Brain inflammation as a biomarker in epilepsy. Biomark Med 2011, 5:607-614.
• [16]Moreno JA, Izquierdo MC, Sanchez-Nino MD, Suarez-Alvarez B, Lopez-Larrea C, Jakubowski A, Blanco J, Ramirez R, Selgas R, Ruiz-Ortega M, Egido J, Ortiz A, Sanz AB: The inflammatory cytokines TWEAK and TNF-alpha reduce renal Klotho expression through NF-kappaB. J Am Soc of Nephrol 2011, 22:1315-1325.
• [17]Thurston RD, Larmonier CB, Majewski PM, Ramalingam R, Midura-Kiela M, Laubitz D, Vandewalle A, Besselsen DG, Muhlbauer M, Jobin C, Kiela PR, Ghishan FK: Tumor necrosis factor and interferon-gamma down-regulate Klotho in mice with colitis. Gastroenterology 2010, 138:1384-1394.
• [18]Wierschke S, Gigout S, Horn P, Lehmann TN, Dehnicke C, Brauer AU, Deisz RA: Evaluating reference genes to normalize gene expression in human epileptogenic brain tissues. Biochem Biophys Res Commun 2010, 403:385-390.
• [19]Becker AJ, Chen J, Paus S, Normann S, Beck H, Elger CE, Wiestler OD, Blumcke I: Transcriptional profiling in human epilepsy: expression array and single cell real-time qRT-PCR analysis reveal distinct cellular gene regulation. Neuroreport 2002, 13:1327-1333.
• [20]Ozbas-Gerceker F, Redeker S, Boer K, Ozguc M, Saygi S, Dalkara T, Soylemezoglu F, Akalan N, Baayen JC, Gorter JA, Aronica E: Serial analysis of gene expression in the hippocampus of patients with mesial temporal lobe epilepsy. Neuroscience 2006, 138:457-474.
• [21]Durrenberger PF, Fernando S, Kashefi SN, Ferrer I, Hauw JJ, Seilhean D, Smith C, Walker R, Al-Sarraj S, Troakes C, Palkovits M, Kasztner M, Huitinga I, Arzberger T, Dexter DT, Kretzschmar H, Reynolds R: Effects of antemortem and postmortem variables on human brain mRNA quality: a BrainNet Europe study. J Neuropathol Exp Neurol 2010, 69:70-81.
• [22]Sopjani M, Alesutan I, Dermaku-Sopjani M, Gu S, Zelenak C, Munoz C, Velic A, Foller M, Rosenblatt KP, Kuro-o M, Lang F: Regulation of the Na+/K+ ATPase by Klotho. FEBS Lett 2011, 585:1759-1764.
• [23]Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J, Malide D, Rovira II, Schimel D, Kuo CJ, Gutkind JS, Hwang PM, Finkel T: Augmented Wnt signaling in a mammalian model of accelerated aging. Science 2007, 317:803-806.
• [24]Brines ML, Tabuteau H, Sundaresan S, Kim J, Spencer DD, de Lanerolle N: Regional distributions of hippocampal Na+, K(+)-ATPase, cytochrome oxidase, and total protein in temporal lobe epilepsy. Epilepsia 1995, 36:371-383.
• [25]Fernandez S, Fernandez AM, Lopez-Lopez C, Torres-Aleman I: Emerging roles of insulin-like growth factor-I in the adult brain. Growth Horm IGF Res 2007, 17:89-95.
• [26]Wang Y, Sun Z: Current understanding of klotho. Ageing Res Rev 2009, 8:43-51.
• [27]Shiozaki M, Yoshimura K, Shibata M, Koike M, Matsuura N, Uchiyama Y, Gotow T: Morphological and biochemical signs of age-related neurodegenerative changes in klotho mutant mice. Neuroscience 2008, 152:924-941.
• [28]Maekawa Y, Ishikawa K, Yasuda O, Oguro R, Hanasaki H, Kida I, Takemura Y, Ohishi M, Katsuya T, Rakugi H: Klotho suppresses TNF-alpha-induced expression of adhesion molecules in the endothelium and attenuates NF-kappaB activation. Endocrine 2009, 35:341-346.
• [29]Witkowski JM, Soroczynska-Cybula M, Bryl E, Smolenska Z, Jozwik A: Klotho–a common link in physiological and rheumatoid arthritis-related aging of human CD4+ lymphocytes. J Immunol 2007, 178:771-777.
• [30]Abraham CR, Chen C, Cuny GD, Glicksman MA, Zeldich E: Small-molecule Klotho enhancers as novel treatment of neurodegeneration. Future Med Chem 2012, 4:1671-1679.
• [31]German DC, Khobahy I, Pastor J, Kuro OM, Liu X: Nuclear localization of Klotho in brain: an anti-aging protein. Neurobiol Aging 2012, 33:1483.
• [32]Falsig J, Porzgen P, Lotharius J, Leist M: Specific modulation of astrocyte inflammation by inhibition of mixed lineage kinases with CEP-1347. J Immunol 2004, 173:2762-2770.
• [33]Nadeau S, Rivest S: Role of microglial-derived tumor necrosis factor in mediating CD14 transcription and nuclear factor kappa B activity in the brain during endotoxemia. J Neurosci 2000, 20:3456-3468.
• [34]Sathyanesan M, Girgenti MJ, Banasr M, Stone K, Bruce C, Guilchicek E, Wilczak-Havill K, Nairn A, Williams K, Sass S, Duman JG, Newton SS: A molecular characterization of the choroid plexus and stress-induced gene regulation. Transl Psychiatry 2012, 2:e139.