J Clin Neurol.  2018 Jul;14(3):327-332. 10.3988/jcn.2018.14.3.327.

Interleukin-6, S-Nitrosothiols, and Neurodegeneration in Different Central Nervous System Demyelinating Disorders: Is There a Relationship?

• Fominykh V
• Vorobyeva
• Onufriev M
• Brylev L
• Zakharova
• Gulyaeva N

• KMID: 2415048
• DOI: http://doi.org/10.3988/jcn.2018.14.3.327

Abstract

BACKGROUND AND PURPOSE
A few groups have suggested that activated cytokines and nitrosative stress are closely involved in the pathogenesis of different demyelinating disorders induced by the neuroinflammatory destruction of neurons. The purpose of this study was to elucidate the associations of cytokines and S-nitrosothiols (RSNO) with the severity of neurodegeneration during relapse in demyelinating disorders of the central nervous system.
METHODS
We measured levels of interleukin-6 (IL-6), erythropoietin, RSNO, and phosphorylated neurofilament heavy chain (pNfh) in cerebrospinal fluid (CSF) samples obtained from patients with different demyelinating disorders: multiple sclerosis (MS, n=52), acute disseminated encephalomyelitis (ADEM, n=9), and neuromyelitis optica spectrum disorders (NMOSD) with aquaporin-4 immunoglobulin G (AQP4-IgG, n=12). We compared these levels with those measured in a control group (n=24).
RESULTS
We found that IL-6 in CSF was elevated in NMOSD with AQP4-IgG and ADEM patients as well as in MS patients after the destruction of soluble IL-6. Erythropoietin levels were lower in MS, while RSNO levels were higher in NMOSD with AQP4-IgG and MS patients than in the control group. CSF pNfh levels were elevated in MS and ADEM patients.
CONCLUSIONS
These results confirm that IL-6 is activated in different demyelinating disorders, with this elevation being more prominent in the CSF of NMOSD with AQP4-IgG and ADEM patients. Moreover, S-nitrosylation is activated in demyelinating disorders with spinal-cord injury and neurodegeneration in these patients. However, we found no correlation between these biochemical markers, and so we could not confirm whether IL-6-mediated nitric oxide production is involved in spinal-cord lesions.

Keyword

interleukin-6; S-nitrosothiols; neurofilament; multiple sclerosis; neuromyelitis optica; acute disseminated encephalomyelitis

MeSH Terms

Biomarkers
Central Nervous System*
Cerebrospinal Fluid
Cytokines
Demyelinating Diseases*
Encephalomyelitis, Acute Disseminated
Erythropoietin
Humans
Immunoglobulin G
Interleukin-6*
Intermediate Filaments
Multiple Sclerosis
Neuromyelitis Optica
Neurons
Nitric Oxide
Recurrence
S-Nitrosothiols*
Biomarkers
Cytokines
Erythropoietin
Immunoglobulin G
Interleukin-6
Nitric Oxide
S-Nitrosothiols

Figure

• 

  Fig. 1 Cytokines, pNfh, and RSNO levels in patients with different demyelinating disorders. Data are median values with 25th and 75th percentiles. A: Serum IL-6 levels were increased in the MS group. B: CSF IL-6 levels before heating were augmented in ADEM and NMOSD with AQP4-IgG but not in MS. C: CSF IL-6 levels after heating were elevated in the RRMS, NMOSD with AQP4-IgG, and ADEM groups. D: CSF EPO levels were decreased in the MS group. E: CSF pNfh levels were elevated in MS and ADEM patients but not in the NMOSD with AQP4-IgG group. F: Serum RSNO levels were increased in the RRMS and NMOSD with AQP4-IgG groups. *Used for statistically significant results (p<0.05). ADEM: acute disseminated encephalomyelitis, AQP4-IgG: aquaporin-4 immunoglobulin G, CSF: cerebrospinal fluid, EPO: erythropoietin, IL-6: interleukin-6, MS: multiple sclerosis, NMO: neuromyelitis optica, NMOSD: neuromyelitis optica spectrum disorders, pNfh: phosphorylated neurofilament heavy chain, RRMS: relapsingremitting multiple sclerosis, RSNO: S-nitrosothiols.

Reference

1. Kallaur AP, Reiche EM, Oliveira SR, Simão AN, Pereira WL, Alfieri DF, et al. Genetic, immune-inflammatory, and oxidative stress biomarkers as predictors for disability and disease progression in multiple sclerosis. Mol Neurobiol. 2017; 54:31–44. PMID: 26732588.

2. Janssens K, Slaets H, Hellings N. Immunomodulatory properties of the IL-6 cytokine family in multiple sclerosis. Ann N Y Acad Sci. 2015; 1351:52–60. PMID: 26100315.

3. Matsushita T, Tateishi T, Isobe N, Yonekawa T, Yamasaki R, Matsuse D, et al. Characteristic cerebrospinal fluid cytokine/chemokine profiles in neuromyelitis optica, relapsing remitting or primary progressive multiple sclerosis. PLoS One. 2013; 8:e61835. PMID: 23637915.

4. Uzawa A, Mori M, Uchida T, Masuda H, Ohtani R, Kuwabara S. Seronegative neuromyelitis optica spectrum disorder patients diagnosed using new diagnostic criteria. Mult Scler. 2016; 22:1371–1375. PMID: 26552730.

5. Chang KH, Ro LS, Lyu RK, Chen CM. Biomarkers for neuromyelitis optica. Clin Chim Acta. 2015; 440:64–71. PMID: 25444748.

6. Chihara N, Aranami T, Sato W, Miyazaki Y, Miyake S, Okamoto T, et al. Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica. Proc Natl Acad Sci U S A. 2011; 108:3701–3706. PMID: 21321193.

7. Wullschleger A, Kapina V, Molnarfi N, Courvoisier DS, Seebach JD, Santiago-Raber ML, et al. Cerebrospinal fluid interleukin-6 in central nervous system inflammatory diseases. PLoS One. 2013; 8:e72399. PMID: 24015240.

8. Uzawa A, Mori M, Masuda H, Ohtani R, Uchida T, Sawai S, et al. Interleukin-6 analysis of 572 consecutive CSF samples from neurological disorders: a special focus on neuromyelitis optica. Clin Chim Acta. 2017; 469:144–149. PMID: 28283439.

9. Araki M, Matsuoka T, Miyamoto K, Kusunoki S, Okamoto T, Murata M, et al. Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study. Neurology. 2014; 82:1302–1306. PMID: 24634453.

10. Beauchemin P, Carruthers R. MS arising during Tocilizumab therapy for rheumatoid arthritis. Mult Scler. 2016; 22:254–256. PMID: 26743640.

11. Kleiter I, Ayzenberg I, Araki M, Yamamura T, Gold R. Tocilizumab, MS, and NMOSD. Mult Scler. 2016; 22:1891–1892. PMID: 27068554.

12. Krumbholz M, Meinl E. B cells in MS and NMO: pathogenesis and therapy. Semin Immunopathol. 2014; 36:339–350. PMID: 24832354.

13. Kaplin AI, Deshpande DM, Scott E, Krishnan C, Carmen JS, Shats I, et al. IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis. J Clin Invest. 2005; 115:2731–2741. PMID: 16184194.

14. Fominykh V, Onufriev MV, Vorobyeva A, Brylev L, Yakovlev AA, Zakharova MN, et al. Increased S-nitrosothiols are associated with spinal cord injury in multiple sclerosis. J Clin Neurosci. 2016; 28:38–42. PMID: 26778356.

15. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011; 69:292–302. PMID: 21387374.

16. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the Mc-Donald criteria. Lancet Neurol. 2018; 17:162–173. PMID: 29275977.

17. Krupp LB, Tardieu M, Amato MP, Banwell B, Chitnis T, Dale RC, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler. 2013; 19:1261–1267. PMID: 23572237.

18. Brownlee WJ, Hardy TA, Fazekas F, Miller DH. Diagnosis of multiple sclerosis: progress and challenges. Lancet. 2017; 389:1336–1346. PMID: 27889190.

19. Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015; 85:177–189. PMID: 26092914.

20. Brailly H, Montero-Julian FA, Zuber CE, Flavetta S, Grassi J, Houssiau F, et al. Total interleukin-6 in plasma measured by immunoassay. Clin Chem. 1994; 40:116–123. PMID: 8287518.

21. Wink DA, Kim S, Miles A, Jourd'heuil D, Grisham MB. Fluorometric techniques for the detection of nitric oxide and metabolites. Curr Protoc Toxicol. 2001; 10:4. PMID: 23045026.

22. Michalopoulou M, Nikolaou C, Tavernarakis A, Alexandri NM, Rentzos M, Chatzipanagiotou S, et al. Soluble interleukin-6 receptor (sIL-6R) in cerebrospinal fluid of patients with inflammatory and non inflammatory neurological diseases. Immunol Lett. 2004; 94:183–189. PMID: 15275965.

23. Padberg F, Feneberg W, Schmidt S, Schwarz MJ, Körschenhausen D, Greenberg BD, et al. CSF and serum levels of soluble interleukin-6 receptors (sIL-6R and sgp130), but not of interleukin-6 are altered in multiple sclerosis. J Neuroimmunol. 1999; 99:218–223. PMID: 10505978.

24. Stelmasiak Z, Kozioł-Montewka M, Dobosz B, Rejdak K. IL-6 and sIL-6R concentration in the cerebrospinal fluid and serum of MS patients. Med Sci Monit. 2001; 7:914–918. PMID: 11535934.

25. Wang H, Wang K, Zhong X, Dai Y, Qiu W, Wu A, et al. Notable increased cerebrospinal fluid levels of soluble interleukin-6 receptors in neuromyelitis optica. Neuroimmunomodulation. 2012; 19:304–308. PMID: 22777162.

26. Barros PO, Cassano T, Hygino J, Ferreira TB, Centurião N, Kasahara TM, et al. Prediction of disease severity in neuromyelitis optica by the levels of interleukin (IL)-6 produced during remission phase. Clin Exp Immunol. 2016; 183:480–489. PMID: 26472479.

27. Bonnan M, Marasescu R, Demasles S, Krim E, Barroso B. No evidence of disease activity (NEDA) in MS should include CSF biology - towards a ‘Disease-Free StatusScore’. Mult Scler Relat Disord. 2017; 11:51–55. PMID: 28104257.

28. Takano R, Misu T, Takahashi T, Sato S, Fujihara K, Itoyama Y. Astrocytic damage is far more severe than demyelination in NMO: a clinical CSF biomarker study. Neurology. 2010; 75:208–216. PMID: 20644148.

29. Kempuraj D, Thangavel R, Natteru PA, Selvakumar GP, Saeed D, Zahoor H, et al. Neuroinflammation induces neurodegeneration. J Neurol Neurosurg Spine. 2016; 1:1003. PMID: 28127589.