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Inflammatory cytokines expression in Wilson’s disease

  • Peng Wu
  • Jianjian Dong
  • Nan ChengEmail author
  • Renmin Yang
  • Yongshen Han
  • Yongzhu HanEmail author
Brief Communication
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Abstract

Background

Wilson’s disease (WD) is an autosomal recessive inherited disorder of copper (Cu) metabolism. Inflammation is a self-defensive reaction aimed at eliminating or neutralizing injurious stimuli, and restoring tissue integrity. Copper deposition may lead to inflammation in the organs and tissues of WD patients.

Objective

The aim of this study was to compare the plasma levels of inflammatory cytokines in patients with WD and healthy group, and also to assess whether inflammatory cytokines affects the clinical manifestation of WD.

Methods

Ninety-nine patients with WD and 32 controls were recruited for this study. Ray Biotech antibody microarray was used to detect the levels of plasma inflammatory cytokines.

Results and conclusion

Our results showed significant increase in T helper (Th) 1 cells (IL-2, TNF-α, and TNF-β), Th2 cells (IL-5, IL-10, and IL-13), and Th17 (IL-23) (p < 0.05). Higher plasma Th 1 cells (IL-2, TNF-α, and TNF-β), Th 2 cells (IL-13), and Th 17 (TGF-β1, IL-23) levels were found in neurological patients compared with control groups (p < 0.01). Besides, we found Th 1 cells (TNF-α and TNF-β), Th 3 (TGF-β1), and Th 17 (IL-23) levels were significantly higher in hepatic and neurological patients (p < 0.05). In addition, the higher Th1 cells (IL-2, TNF-α, and TNF-β), Th2 cells (IL-13), and Th17 (TGF-β1, IL-23) and the course of WD were associated with the severity of the neurological symptoms for WD patients. Altogether, our results indicated that dysregulation of cytokines, mainly increased expression of cytokines and chemokines, occurred in WD patients.

Keywords

Wilson’s disease Inflammation Cytokine Copper 

Notes

Compliance with ethical standards

Ethical statement

The study was approved by the institutional review Hospital Affiliated to Institute of Neurology, Anhui University of Traditional Chinese Medicine. All patients provided written informed consent.

References

  1. 1.
    Seo JK (2006) Wilson’s disease: an update. Nat Clin Pract Neurol 2:482–493Google Scholar
  2. 2.
    Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW (1993) The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet 5:327–337PubMedCrossRefGoogle Scholar
  3. 3.
    Thomas GR, Forbes JR, Roberts EA, Walshe JM, Cox DW (1995) The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet 9:210–217PubMedCrossRefGoogle Scholar
  4. 4.
    Loudianos G, Lepori MB, Mameli E, Dessì V, Zappu A (2014) Wilson disease. Prilozi 35(1):93–98PubMedGoogle Scholar
  5. 5.
    Schmalz G, Schuster U, Schweikl H (1998) Influence of metals on IL-6 release in vitro. Biomaterials 19(18):1689–1694PubMedCrossRefGoogle Scholar
  6. 6.
    Medici V, Shibata NM, Kharbanda KK, LaSalle JM, Woods R, Liu S, Engelberg JA, Devaraj S, Török NJ, Jiang JX, Havel PJ, Lönnerdal B, Kim K, Halsted CH (2013) Wilson's disease: changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease. Hepatology 57(2):555–565PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Lu J, Wu DM, Zheng YL, Sun DX, Hu B, Shan Q, Zhang ZF, Fan SH (2009) Trace amounts of copper exacerbate beta amyloid-induced neurotoxicity in the cholesterol fed mice through TNF-mediated inflammatory pathway. Brain Behav Immun 23(2):193–203PubMedCrossRefGoogle Scholar
  8. 8.
    Spisni E, Valerii MC, Manerba M, Strillacci A, Polazzi E, Mattia T, Griffoni C, Tomasi V (2009) Effect of copper on extracellular levels of key pro-inflammatory molecules in hypothalamic GN11 and primary neurons. Neurotoxicology 30(4):605–612PubMedCrossRefGoogle Scholar
  9. 9.
    Terwel D, Löschmann YN, Schmidt HH, Schöler HR, Cantz T, Heneka MT (2011) Neuroinflammatory and behavioural changes in the Atp7B mutant mouse model of Wilson’s disease. J Neurochem 118(1):105–112PubMedCrossRefGoogle Scholar
  10. 10.
    Kim YK, Na KS, Myint AM, Leonard BE (2015) The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression. Prog Neuro-Psychopharmacol Biol Psychiatry 64:277CrossRefGoogle Scholar
  11. 11.
    Freeman LC, Ting JP (2015) The pathogenic role of the inflammasome in neurodegenerative diseases. J Neurochem 136:29–38PubMedCrossRefGoogle Scholar
  12. 12.
    Centonze D, Muzio L, Rossi S, Cavasinni F, De Chiara V, Bergami A, Musella A, D’Amelio M, Cavallucci V, Martorana A, Bergamaschi A, Cencioni MT, Diamantini A, Butti E, Comi G, Bernardi G, Cecconi F, Battistini L, Furlan R, Martino G (2009) Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci 29:3442–3452PubMedCrossRefGoogle Scholar
  13. 13.
    Rossi S, Furlan R, De Chiara V, Motta C, Studer V, Mori F, Musella A, Bergami A, Muzio L, Bernardi G, Battistini L, Martino G, Centonze D (2012) Interleukin-1 β causes synaptic hyperexcitability in multiple sclerosis. Ann Neurol 71:76–83PubMedCrossRefGoogle Scholar
  14. 14.
    Froger N, Orellana JA, Calvo CF, Amigou E, Kozoriz MG, Naus CC, Sáez JC, Giaume C (2010) Inhibition of cytokine-induced connexin43 hemichannel activity in astrocytes is neuro- protective. Mol Cell Neurosci 45:37–46PubMedCrossRefGoogle Scholar
  15. 15.
    Lai AY, Swayze RD, El-Husseini A, Song C (2006) Interleukin-1 beta modulates AMPA receptor expression and phosphorylation in hippocampal neurons. J Neuroimmunol 175:97–106PubMedCrossRefGoogle Scholar
  16. 16.
    Tolosa L, Caraballo-Miralles V, Olmos G, Lladó J (2011) TNF-α potentiates glutamate-induced spinal cord motoneuron death via NF-kB. Mol Cell Neurosci 46:176–186PubMedCrossRefGoogle Scholar
  17. 17.
    Aggarwal A, Aggarwal N, Nagral A, Jankharia G, Bhatt M (2009) A novel global assessment scale for Wilson's disease (GAS for WD). Mov Disord 24(4):509–518PubMedCrossRefGoogle Scholar
  18. 18.
    Di Filippo M, Chiasserini D, Tozzi A, Picconi B, Calabresi P (2010) Mitochondria and the link between neuroinflammation and neurodegenertion. J Alzheimers Dis 20:369–379CrossRefGoogle Scholar
  19. 19.
    Schmalz G, Schuster U, Schweikl H (1998) Influence of metalson IL-6 release in vitro. Biomaterials 19(18):1689–1694PubMedCrossRefGoogle Scholar
  20. 20.
    Aktas O, Ullrich O, Infante-Duarte C, Nitsch R, Zipp F (2007) Neuronal damage in brain inflammation. Arch Neurol 64:185–189PubMedCrossRefGoogle Scholar
  21. 21.
    Heneka MT, O’Banion MK (2007) Inflammatory processes in Alzheimer’s disease. J Neuroimmunol 184:69–91PubMedCrossRefGoogle Scholar
  22. 22.
    Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson, s disease: a target for neuroprotection? Lancet Neurol 8:382–397PubMedCrossRefGoogle Scholar
  23. 23.
    Bjorkqvist M, Wild EJ, Tabrizi SJ (2009) Harnessing immune alterations in neurodegenerative diseases. Neuron 64:21–24PubMedCrossRefGoogle Scholar
  24. 24.
    Verkhratsky A, Parpura V, Pekna M, Pekny M, Sofroniew M (2014) Glia in the pathogenesis of neurodegenerative diseases. Biochem Soc Trans 42:1291–1301PubMedCrossRefGoogle Scholar
  25. 25.
    Tansey M, Tran T, Lee JK (2009) Neuroinflammation in Parkinson’s disease. J NeuroImmune Pharmacol 4:419–429PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Kalita J, Kumar V, Misra UK, Ranjan A, Khan H, Konwar R (2014) A study of oxidative stress, cytokines and glutamate in Wilson disease and their asymptomatic siblings. J Neuroimmunol 274(1–2):141–148PubMedCrossRefGoogle Scholar
  27. 27.
    Choo XY, Alukaidey L, White AR, Grubman A (2013) Neuroinflammation and copper in Alzheimer's disease [J]. Int J Alzheimers Dis 2013:145345PubMedPubMedCentralGoogle Scholar
  28. 28.
    Weberpals M, Hermes M, Hermann S, Kummer MP, Terwel D, Semmler A, Berger M, Scha fers M, Heneka MT (2009) NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits. J Neurosci 29:14177–14184PubMedCrossRefGoogle Scholar
  29. 29.
    Videla LA, Fernández V, Tapia G, Varela P (2003) Oxidative stress-mediated hepatotoxicity of iron and copper: role of Kupffer cells. Biometals 16(1):103–111PubMedCrossRefGoogle Scholar
  30. 30.
    Harry GJ, Kraft AD (2008) Neuroinflammation and microglia: considerations and approaches for neurotoxicity assessment. Expert Opin Drug Metab Toxicol 4(10):1265–1277PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Lehnardt S (2012) Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 58:253–263Google Scholar
  32. 32.
    Streit WJ, Walter SA, Pennell NA (1999) Reactive microgliosis. Prog Neurobiol 57(6):563–581PubMedCrossRefGoogle Scholar
  33. 33.
    Kodama H, Okabe I, Yanagisawa M, Nomiyama H, Nomiyama K, Nose O, Kamoshita S (1988) Does CSF copper level in Wilson disease reflect copper accumulation in the brain? Pediatr Neurol 4(1):35–37PubMedCrossRefGoogle Scholar
  34. 34.
    Horoupian DS, Sternlieb I, Scheinberg IH (1988) Neuropathological findings in penicillamine-treated patients with Wilson’s disease. Clin Neuropathol 7(2):62–67PubMedGoogle Scholar

Copyright information

© Fondazione Società Italiana di Neurologia 2019

Authors and Affiliations

  1. 1.College of integrated traditional Chinese and Western MedicineAnhui University of Traditional Chinese MedicineHefeiChina
  2. 2.Hospital Affiliated to Institute of NeurologyAnhui University of Traditional Chinese MedicineHefeiChina

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