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Open Access 01-12-2012 | Research

Carriers of the fragile X mental retardation 1 (FMR1) premutation allele present with increased levels of cytokine IL-10

Authors: Diana Marek, Stephanie Papin, Kim Ellefsen, Julien Niederhauser, Nathalie Isidor, Adriana Ransijn, Lucienne Poupon, Francois Spertini, Giuseppe Pantaleo, Sven Bergmann, Jacques S Beckmann, Sebastien Jacquemont, Goranka Tanackovic

Published in: Journal of Neuroinflammation | Issue 1/2012

Abstract

Background

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited late-onset neurodegenerative disorder, characterized both by neurological and cognitive deficits. It is caused by the expansion of CGG repeats (55 to 200 repeats) in the noncoding region of the fragile X mental retardation 1 (FMR1) gene. Abnormal immunological patterns are often associated with neurodegenerative disorders and implicated in their etiology. We therefore investigated the immune status of FXTAS patients, which had not been assessed prior to this study.

Method

Peripheral blood mononuclear cells (PBMCs) were collected from 15 asymptomatic FMR1 premutation carriers and 20 age-matched controls. Concentrations of three cytokines (IL-6, IL-8, IL-10) were measured in PBMC supernatants using ELISA assays.

Results

We found a significant increase in the concentration of the major anti-inflammatory cytokine IL-10 in supernatants of PBMCs derived from premutation carriers, when compared with controls (P = 0.019). This increase correlated significantly with the number of CGG repeats (P = 0.002).

Conclusions

Elevated IL-10 levels were observed in all premutation carriers, before appearance of the classical neurological symptoms; therefore, IL-10 may be one of the early biomarkers of FXTAS.

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Jacquemont S, Hagerman RJ, Leehey M, Grigsby J, Zhang L, Brunberg JA, Greco C, Des Portes V, Jardini T, Levine R, Berry-Kravis E, Brown WT, Schaeffer S, Kissel J, Tassone F, Hagerman PJ: Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 2003, 72:869–878.CrossRefPubMedPubMedCentral

Coffey SM, Cook K, Tartaglia N, Tassone F, Nguyen DV, Pan R, Bronsky HE, Yuhas J, Borodyanskaya M, Grigsby J, Doerflinger M, Hagerman PJ, Hagerman RJ: Expanded clinical phenotype of women with the FMR1 premutation. Am J Med Genet A 2008, 146A:1009–1016.CrossRefPubMedPubMedCentral

Gleicher N, Weghofer A, Lee IH, Barad DH: FMR1 genotype with autoimmunity-associated polycystic ovary-like phenotype and decreased pregnancy chance. PLoS One 2010, 5:e15303.CrossRefPubMedPubMedCentral

Garcia-Arocena D, Hagerman PJ: Advances in understanding the molecular basis of FXTAS. Hum Mol Genet 2010, 19:R83-R89.CrossRefPubMedPubMedCentral

Hagerman RJ, Hagerman PJ: The fragile X premutation: into the phenotypic fold. Curr Opin Genet Dev 2002, 12:278–283.CrossRefPubMed

Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, Grigsby J, Gage B, Hagerman PJ: Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 2001, 57:127–130.CrossRefPubMed

Hessl D, Tassone F, Loesch DZ, Berry-Kravis E, Leehey MA, Gane LW, Barbato I, Rice C, Gould E, Hall DA, Grigsby J, Wegelin JA, Harris S, Lewin F, Weinberg D, Hagerman PJ, Hagerman RJ: Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation. Am J Med Genet B Neuropsychiatr Genet 2005, 139B:115–121.CrossRefPubMed

Tassone F, Hagerman RJ, Garcia-Arocena D, Khandjian EW, Greco CM, Hagerman PJ: Intranuclear inclusions in neural cells with premutation alleles in fragile X associated tremor/ataxia syndrome. J Med Genet 2004, 41:e43.CrossRefPubMedPubMedCentral

Greco CM, Hagerman RJ, Tassone F, Chudley AE, Del Bigio MR, Jacquemont S, Leehey M, Hagerman PJ: Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 2002, 125:1760–1771.CrossRefPubMed

10.

Iwahashi CK, Yasui DH, An HJ, Greco CM, Tassone F, Nannen K, Babineau B, Lebrilla CB, Hagerman RJ, Hagerman PJ: Protein composition of the intranuclear inclusions of FXTAS. Brain 2006, 129:256–271.CrossRefPubMed

11.

Klegeris A, McGeer EG, McGeer PL: Therapeutic approaches to inflammation in neurodegenerative disease. Curr Opin Neurol 2007, 20:351–357.CrossRefPubMed

12.

Liu B, Hong JS: Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 2003, 304:1–7.CrossRefPubMed

13.

Gao HM, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ, Lee VM: Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J Neurosci 2008, 28:7687–7698.CrossRefPubMedPubMedCentral

14.

Zipp F, Aktas O: The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci 2006, 29:518–527.CrossRefPubMed

15.

Gao HM, Liu B, Zhang W, Hong JS: Novel anti-inflammatory therapy for Parkinson’s disease. Trends Pharmacol Sci 2003, 24:395–401.CrossRefPubMed

16.

Liu B, Du L, Hong JS: Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. J Pharmacol Exp Ther 2000, 293:607–617.PubMed

17.

Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, Choi DK, Ischiropoulos H, Przedborski S: Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 2002, 22:1763–1771.PubMed

18.

Zhang W, Wang T, Qin L, Gao HM, Wilson B, Ali SF, Hong JS, Liu B: Neuroprotective effect of dextromethorphan in the MPTP Parkinson’s disease model: role of NADPH oxidase. FASEB J 2004, 18:589–591.PubMed

19.

Chen H, Jacobs E, Schwarzschild MA, McCullough ML, Calle EE, Thun MJ, Ascherio A: Nonsteroidal anti-inflammatory drug use and the risk for Parkinson’s disease. Ann Neurol 2005, 58:963–967.CrossRefPubMed

20.

Gao X, Chen H, Schwarzschild MA, Ascherio A: Use of ibuprofen and risk of Parkinson disease. Neurology 2011, 76:863–869.CrossRefPubMedPubMedCentral

21.

McGeer EG, McGeer PL: The role of anti-inflammatory agents in Parkinson’s disease. CNS Drugs 2007, 21:789–797.CrossRefPubMed

22.

Weggen S, Rogers M, Eriksen J: NSAIDs: small molecules for prevention of Alzheimer’s disease or precursors for future drug development? Trends Pharmacol Sci 2007, 28:536–543.CrossRefPubMed

23.

Leehey MA, Berry-Kravis E, Goetz CG, Zhang L, Hall DA, Li L, Rice CD, Lara R, Cogswell J, Reynolds A, Gane L, Jacquemont S, Tassone F, Grigsby J, Hagerman RJ, Hagerman PJ: FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology 2008, 70:1397–1402.CrossRefPubMed

24.

Bourgeois JA, Seritan AL, Casillas EM, Hessl D, Schneider A, Yang Y, Kaur I, Cogswell JB, Nguyen DV, Hagerman RJ: Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers. J Clin Psychiatry 2011, 72:175–182.CrossRefPubMed

25.

Kogan CS, Turk J, Hagerman RJ, Cornish KM: Impact of the Fragile X mental retardation 1 (FMR1) gene premutation on neuropsychiatric functioning in adult males without fragile X-associated Tremor/Ataxia syndrome: a controlled study. Am J Med Genet B Neuropsychiatr Genet 2008, 147B:859–872.CrossRefPubMed

26.

Björkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N, Raibon E, Lee RV, Benn CL, Soulet D, Magnusson A, Woodman B, Landles C, Pouladi MA, Hayden MR, Khalili-Shirazi A, Lowdell MW, Brundin P, Bates GP, Leavitt BR, Möller T, Tabrizi SJ: A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J Exp Med 2008, 205:1869–1877.CrossRefPubMedPubMedCentral

27.

Rentzos M, Nikolaou C, Andreadou E, Paraskevas GP, Rombos A, Zoga M, Tsoutsou A, Boufidou F, Kapaki E, Vassilopoulos D: Circulating interleukin-10 and interleukin-12 in Parkinson’s disease. Acta Neurol Scand 2009, 119:332–337.CrossRefPubMed

28.

Roze E, Bonnet C, Betuing S, Caboche J: Huntington’s disease. Adv Exp Med Biol. 2010, 685:45–63.CrossRefPubMed

29.

Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG: Does neuroinflammation fan the flame in neurodegenerative diseases? Mol Neurodegener 2009, 4:47.CrossRefPubMedPubMedCentral

30.

Minghetti L: Role of inflammation in neurodegenerative diseases. Curr Opin Neurol 2005, 18:315–321.CrossRefPubMed

31.

O’Garra A, Barrat FJ, Castro AG, Vicari A, Hawrylowicz C: Strategies for use of IL-10 or its antagonists in human disease. Immunol Rev 2008, 223:114–131.CrossRefPubMed

32.

O’Garra A, Vieira P: T(H)1 cells control themselves by producing interleukin-10. Nat Rev Immunol 2007, 7:425–428.CrossRefPubMed

33.

Saraiva M, O’Garra A: The regulation of IL-10 production by immune cells. Nat Rev Immunol 2010, 10:170–181.CrossRefPubMed

34.

Hmadcha A, De Diego Y, Pintado E: Assessment of FMR1 expression by reverse transcriptase-polymerase chain reaction of KH domains. J Lab Clin Med 1998, 131:170–173.CrossRefPubMed

35.

Dace DS, Khan AA, Stark JL, Kelly J, Cross AH, Apte RS: Interleukin-10 overexpression promotes Fas-ligand-dependent chronic macrophage-mediated demyelinating polyneuropathy. PLoS One 2009, 4:e7121.CrossRefPubMedPubMedCentral

Title: Carriers of the fragile X mental retardation 1 (FMR1) premutation allele present with increased levels of cytokine IL-10
Authors: Diana Marek
Stephanie Papin
Kim Ellefsen
Julien Niederhauser
Nathalie Isidor
Adriana Ransijn
Lucienne Poupon
Francois Spertini
Giuseppe Pantaleo
Sven Bergmann
Jacques S Beckmann
Sebastien Jacquemont
Goranka Tanackovic
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/1742-2094-9-238

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Carriers of the fragile X mental retardation 1 (FMR1) premutation allele present with increased levels of cytokine IL-10

Abstract

Background

Method

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Method

Results

Conclusions

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