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Journal of Neuroinflammation

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Open Access 01-12-2017 | Research

Increased interleukin-27 cytokine expression in the central nervous system of multiple sclerosis patients

Authors: Patrice H. Lalive, Mario Kreutzfeldt, Odile Devergne, Imke Metz, Wolfgang Bruck, Doron Merkler, Caroline Pot

Published in: Journal of Neuroinflammation | Issue 1/2017

Abstract

Background

Multiple sclerosis (MS) is an autoimmune disorder characterized by chronic inflammation, demyelination, and neuronal damage. During autoimmunity, cytokines are important mediators of the inflammation. In this line, interleukin-27 (IL-27) modulates inflammation and can be produced directly at inflammatory sites such as in the joints during rheumatoid arthritis or in the central nervous system (CNS) during MS. While in animal models of MS, treatment with IL-27 decreases the disease severity, its role in humans is not clearly established and it is not known if IL-27 could be detected in the cerebrospinal fluid (CSF) of MS patients.

Methods

In this study, we measured IL-27 levels using a quantitative enzyme-linked immunosorbent assay in CSF of patients with relapsing remitting multiple sclerosis (RRMS), isolated optic neuritis (ON) and non-inflammatory neurological disease (NIND) as well as in the sera of healthy donors (HD) and RRMS patients undergoing different disease modifying treatments. We further confirmed by immunohistology of patient biopsies the identity of IL-27 producing cells in the brain of active MS lesions.

Results

We observed that IL-27 levels are increased in the CSF but not in the sera of RRMS compared to HD. We confirmed that IL-27 is expressed in active MS plaques by astrocytes of MS patients.

Conclusions

Our results point toward a local secretion of IL-27 in the CNS that is increased during autoimmune processes. We propose that local production of IL-27 could sign the induction of a regulatory response that promotes inflammation’s resolution. The effect of new immunomodulatory therapies on cerebral IL-27 production could be used to understand the biology of IL-27 in MS disease.

Pot C, Apetoh L, Awasthi A, Kuchroo VK. Induction of regulatory Tr1 cells and inhibition of T(H)17 cells by IL-27. Semin Immunol. 2011;23(6):438–45.CrossRefPubMedPubMedCentral

Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M, Flavell RA, et al. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol. 2007;8(12):1380–9.CrossRefPubMed

Fitzgerald DC, Zhang GX, El-Behi M, Fonseca-Kelly Z, Li H, Yu S, et al. Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat Immunol. 2007;8(12):1372–9.CrossRefPubMed

Fitzgerald DC, Ciric B, Touil T, Harle H, Grammatikopolou J, Das Sarma J, et al. Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis. J Immunol. 2007;179(5):3268–75.CrossRefPubMed

Peters A, Fowler KD, Chalmin F, Merkler D, Kuchroo VK, Pot C. IL-27 induces Th17 differentiation in the absence of STAT1 signaling. J Immunol. 2015;195(9):4144–53.CrossRefPubMedPubMedCentral

Sweeney CM, Lonergan R, Basdeo SA, Kinsella K, Dungan LS, Higgins SC, et al. IL-27 mediates the response to IFN-beta therapy in multiple sclerosis patients by inhibiting Th17 cells. Brain Behav Immun. 2011;25(6):1170–81.CrossRefPubMed

Severa M, Rizzo F, Giacomini E, Annibali V, Gafa V, Romano S, et al. IFN-beta therapy regulates TLR7-mediated response in plasmacytoid dendritic cells of multiple sclerosis patients influencing an anti-inflammatory status. J Interf Cytokine Res. 2015;35(9):668–81.CrossRef

Mindur JE, Valenzuela RM, Yadav SK, Boppana S, Dhib-Jalbut S, Ito K. IL-27: a potential biomarker for responders to glatiramer acetate therapy. J Neuroimmunol. 2017;304:21–8.CrossRefPubMed

Tanida S, Yoshitomi H, Ishikawa M, Kasahara T, Murata K, Shibuya H, et al. IL-27-producing CD14(+) cells infiltrate inflamed joints of rheumatoid arthritis and regulate inflammation and chemotactic migration. Cytokine. 2011;55(2):237–44.CrossRefPubMed

10.

Li J, Gran B, Zhang GX, Rostami A, Kamoun M. IL-27 subunits and its receptor (WSX-1) mRNAs are markedly up-regulated in inflammatory cells in the CNS during experimental autoimmune encephalomyelitis. J Neurol Sci. 2005;232(1–2):3–9.CrossRefPubMed

11.

Sonobe Y, Yawata I, Kawanokuchi J, Takeuchi H, Mizuno T, Suzumura A. Production of IL-27 and other IL-12 family cytokines by microglia and their subpopulations. Brain Res. 2005;1040(1–2):202–7.CrossRefPubMed

12.

Senecal V, Deblois G, Beauseigle D, Schneider R, Brandenburg J, Newcombe J, et al. Production of IL-27 in multiple sclerosis lesions by astrocytes and myeloid cells: modulation of local immune responses. Glia. 2016;64(4):553–69.CrossRefPubMed

13.

Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol. 2005;58(6):840–6.CrossRefPubMed

14.

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(8):e72399.CrossRefPubMedPubMedCentral

15.

Bo L, Mork S, Kong PA, Nyland H, Pardo CA, Trapp BD. Detection of MHC class II-antigens on macrophages and microglia, but not on astrocytes and endothelia in active multiple sclerosis lesions. J Neuroimmunol. 1994;51(2):135–46.CrossRefPubMed

16.

Bruck W, Porada P, Poser S, Rieckmann P, Hanefeld F, Kretzschmar HA, et al. Monocyte/macrophage differentiation in early multiple sclerosis lesions. Ann Neurol. 1995;38(5):788–96.CrossRefPubMed

17.

Bruck W, Schmied M, Suchanek G, Bruck Y, Breitschopf H, Poser S, et al. Oligodendrocytes in the early course of multiple sclerosis. Ann Neurol. 1994;35(1):65–73.CrossRefPubMed

18.

Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47(6):707–17.CrossRefPubMed

19.

Yoshida H, Hunter CA. The immunobiology of interleukin-27. Annu Rev Immunol. 2015;33:417–43.CrossRefPubMed

20.

Sosvorova L, Kanceva R, Vcelak J, Kancheva L, Mohapl M, Starka L, et al. The comparison of selected cerebrospinal fluid and serum cytokine levels in patients with multiple sclerosis and normal pressure hydrocephalus. Neuro Endocrinol Lett. 2015;36(6):564–71.PubMed

21.

Ji AL, Liu ZH, Chen WW, Huang WJ. The clinical significance of level changes of hs-CRP, IL-10 and TNF for patients with MS during active and relieving period. Eur Rev Med Pharmacol Sci. 2016;20(20):4274–6.PubMed

22.

Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J, et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells. Immunity. 2002;16(6):779–90.CrossRefPubMed

23.

Collison LW, Pillai MR, Chaturvedi V, Vignali DAA. Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35-and IL-10-dependent manner. J Immunol. 2009;182(10):6121–8.CrossRefPubMedPubMedCentral

24.

Ye S, Wu J, Zhou L, Lv Z, Xie H, Zheng S. Interleukin-35: the future of hyperimmune-related diseases? J Interf Cytokine Res. 2013;33(6):285–91.CrossRef

25.

Shen P, Roch T, Lampropoulou V, O'Connor RA, Stervbo U, Hilgenberg E, et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 2014;507(7492):366–70.CrossRefPubMedPubMedCentral

Title: Increased interleukin-27 cytokine expression in the central nervous system of multiple sclerosis patients
Authors: Patrice H. Lalive
Mario Kreutzfeldt
Odile Devergne
Imke Metz
Wolfgang Bruck
Doron Merkler
Caroline Pot
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-017-0919-1

At a glance: The STEP trials

Springer Medicine

Increased interleukin-27 cytokine expression in the central nervous system of multiple sclerosis patients

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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