Research Article| Volume 337, 577062, December 15, 2019

Download started.


Impact of interferon β-1b, interferon β-1a and fingolimod therapies on serum interleukins-22, 32α and 34 concentrations in patients with relapsing-remitting multiple sclerosis

  • Marwa A. Abdel-Dayem
    Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt

    Department of Pharmacology and Toxicology, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt
    Search for articles by this author
  • Mohamed E. Shaker
    Corresponding author at: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
    Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt

    Department of Pharmacology, Faculty of Pharmacy, Jouf University, Sakaka 2014, Saudi Arabia
    Search for articles by this author
  • Nariman M. Gameil
    Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
    Search for articles by this author
Published:September 06, 2019DOI:


      • Serum ILs-22, 32α and 34 concentrations were assessed in multiple sclerosis.
      • Serum IL-22 concentration positively correlated with EDSS value.
      • Serum IL-22 concentration negatively correlated with the treatment duration.
      • Serum IL-22 concentration may be a potential marker for multiple sclerosis severity.
      • Serum IL-22 concentration may be a good predictor of treatment efficacy.


      Interleukins (ILs)-22, 32α and 34 were monitored in the sera of relapsing-remitting multiple sclerosis (RRMS) patients at different time intervals with or without interferon β-1b, interferon β-1a and fingolimod treatments. The results showed that sera of untreated RRMS patients were statistically higher in concentration of IL-22 (P < .001), but not IL-32α and IL-34, than those of healthy individuals. Interestingly, interferon β-1b, interferon β-1a and fingolimod treatments led to a significant decrease of serum concentrations of ILs-22 and 32α, but not 34, at 6 and 12 months of treatment, compared to their initial concentrations before initiating therapy. The correlation analysis revealed that the changes of serum IL-22 (r = 0.814) and, to a lesser extent, IL-32α (r = 0.381) concentrations were positively correlated with those of expanded disability status score. In conclusion, serum IL-22 concentration may be a potential marker for MS disease severity and efficacy of treatment.

      Graphical abstract


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Neuroimmunology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Almolda B.
        • Costa M.
        • Montoya M.
        • González B.
        • Castellano B.
        Increase in Th17 and T-reg lymphocytes and decrease of IL22 correlate with the recovery phase of acute EAE in rat.
        PLoS One. 2011; 6 (:e27473-e)
        • Dahl C.A.
        • Schall R.P.
        • He H.L.
        • Cairns J.S.
        Identification of a novel gene expressed in activated natural killer cells and T cells.
        Journal of immunology (Baltimore, Md : 1950). 1992; 148: 597-603
        • Greter M.
        • Lelios I.
        • Pelczar P.
        • Hoeffel G.
        • Price J.
        • Leboeuf M.
        • et al.
        Stroma-derived interleukin-34 controls the development and maintenance of langerhans cells and the maintenance of microglia.
        Immunity. 2012; 37: 1050-1060
        • Gui M.
        • Zhang H.
        • Zhong K.
        • Li Y.
        • Sun J.
        • Wang L.
        Clinical significance of interleukin-32 expression in patients with rheumatoid arthritis.
        Asian Pac. J. Allergy Immunol. 2013; 31: 73-78
        • Jia Y.
        • Jing J.
        • Bai Y.
        • Li Z.
        • Liu L.
        • Luo J.
        • et al.
        Amelioration of experimental autoimmune encephalomyelitis by plumbagin through down-regulation of JAK-STAT and NF-kappaB signaling pathways.
        PLoS One. 2011; 6e27006
        • Jin S.
        • Sonobe Y.
        • Kawanokuchi J.
        • Horiuchi H.
        • Cheng Y.
        • Wang Y.
        • et al.
        Interleukin-34 restores blood-brain barrier integrity by upregulating tight junction proteins in endothelial cells.
        PLoS One. 2014; 9 (e115981-e)
        • Jung M.Y.
        • Son M.H.
        • Kim S.H.
        • Cho D.
        • Kim T.S.
        IL-32gamma induces the maturation of dendritic cells with Th1- and Th17-polarizing ability through enhanced IL-12 and IL-6 production.
        Journal of immunology (Baltimore, Md : 1950). 2011; 186: 6848-6859
        • Kebir H.
        • Kreymborg K.
        • Ifergan I.
        • Dodelet-Devillers A.
        • Cayrol R.
        • Bernard M.
        • et al.
        Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation.
        Nat. Med. 2007; 13: 1173-1175
        • Kim K.W.
        • Kim H.R.
        • Park J.Y.
        • Park J.S.
        • Oh H.J.
        • Woo Y.J.
        • et al.
        Interleukin-22 promotes osteoclastogenesis in rheumatoid arthritis through induction of RANKL in human synovial fibroblasts.
        Arthritis Rheum. 2012; 64: 1015-1023
        • Koudriavtseva T.
        • Mainero C.
        Neuroinflammation, neurodegeneration and regeneration in multiple sclerosis: intercorrelated manifestations of the immune response.
        Neural Regen. Res. 2016; 11: 1727-1730
        • Lejeune D.
        • Dumoutier L.
        • Constantinescu S.
        • Kruijer W.
        • Schuringa J.J.
        • Renauld J.C.
        Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10.
        The Journal of biological chemistry. 2002; 277: 33676-33682
        • Luo J.
        • Elwood F.
        • Britschgi M.
        • Villeda S.
        • Zhang H.
        • Ding Z.
        • et al.
        Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival.
        J. Exp. Med. 2013; 210: 157-172
        • Ma D.
        • Doi Y.
        • Jin S.
        • Li E.
        • Sonobe Y.
        • Takeuchi H.
        • et al.
        TGF-beta induced by interleukin-34-stimulated microglia regulates microglial proliferation and attenuates oligomeric amyloid beta neurotoxicity.
        Neurosci. Lett. 2012; 529: 86-91
        • Maddur M.S.
        • Miossec P.
        • Kaveri S.V.
        • Bayry J.
        Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies.
        Am. J. Pathol. 2012; 181: 8-18
        • Mizuno T.
        • Doi Y.
        • Mizoguchi H.
        • Jin S.
        • Noda M.
        • Sonobe Y.
        • et al.
        Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-beta neurotoxicity.
        Am. J. Pathol. 2011; 179: 2016-2027
        • Morsaljahan Z.
        • Rafiei A.
        • Valadan R.
        • Abedini M.
        • Pakseresht M.
        • Khajavi R.
        Association between interleukin-32 polymorphism and multiple sclerosis.
        J. Neurol. Sci. 2017; 379: 144-150
        • Na S.J.
        • So S.H.
        • Lee K.O.
        • Choi Y.C.
        Elevated serum level of interleukin-32alpha in the patients with myasthenia gravis.
        J. Neurol. 2011; 258: 1865-1870
        • Nold M.F.
        • Nold-Petry C.A.
        • Pott G.B.
        • Zepp J.A.
        • Saavedra M.T.
        • Kim S.H.
        • et al.
        Endogenous IL-32 controls cytokine and HIV-1 production.
        Journal of immunology (Baltimore, Md : 1950). 2008; 181: 557-565
        • Nold-Petry C.A.
        • Nold M.F.
        • Zepp J.A.
        • Kim S.H.
        • Voelkel N.F.
        • Dinarello C.A.
        IL-32-dependent effects of IL-1beta on endothelial cell functions.
        Proc. Natl. Acad. Sci. U. S. A. 2009; 106: 3883-3888
        • Pérez-Cerdá F.
        • Sánchez-Gómez M.V.
        • Matute C.
        The link of inflammation and neurodegeneration in progressive multiple sclerosis.
        Multiple Sclerosis and Demyelinating Disorders. 2016; 1: 9
        • Perriard G.
        • Mathias A.
        • Enz L.
        • Canales M.
        • Schluep M.
        • Gentner M.
        • et al.
        Interleukin-22 is increased in multiple sclerosis patients and targets astrocytes.
        J. Neuroinflammation. 2015; 12: 119
        • Rolla S.
        • Bardina V.
        • De Mercanti S.
        • Quaglino P.
        • De Palma R.
        • Gned D.
        • et al.
        Th22 cells are expanded in multiple sclerosis and are resistant to IFN-beta.
        J. Leukoc. Biol. 2014; 96: 1155-1164
        • Trifari S.
        • Kaplan C.D.
        • Tran E.H.
        • Crellin N.K.
        • Spits H.
        Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells.
        Nat. Immunol. 2009; 10: 864-871
        • Wang Y.
        • Colonna M.
        Interkeukin-34, a cytokine crucial for the differentiation and maintenance of tissue resident macrophages and Langerhans cells.
        Eur. J. Immunol. 2014; 44: 1575-1581
        • Wang H.
        • Wang K.
        • Wang C.
        • Xu F.
        • Qiu W.
        • Hu X.
        Increased plasma interleukin-32 expression in patients with neuromyelitis optica.
        J. Clin. Immunol. 2013; 33: 666-670
        • Wang Y.
        • Zhou B.
        • Zhao Y.
        • Yu X.
        • Liu Y.
        • Zhang L.
        Association of Plasma IL-32 levels and gene polymorphisms with systemic lupus erythematosus in Chinese Han population.
        Dis. Markers. 2016; 20162460206
        • Wing A.C.
        • Hygino J.
        • Ferreira T.B.
        • Kasahara T.M.
        • Barros P.O.
        • Sacramento P.M.
        • et al.
        Interleukin-17- and interleukin-22-secreting myelin-specific CD4(+) T cells resistant to corticoids are related with active brain lesions in multiple sclerosis patients.
        Immunology. 2016; 147: 212-220
        • Xu W.
        • Li R.
        • Dai Y.
        • Wu A.
        • Wang H.
        • Cheng C.
        • et al.
        IL-22 secreting CD4+ T cells in the patients with neuromyelitis optica and multiple sclerosis.
        J. Neuroimmunol. 2013; 261: 87-91
        • Yang X.
        • Zheng S.G.
        Interleukin-22: a likely target for treatment of autoimmune diseases.
        Autoimmun. Rev. 2014; 13: 615-620
        • Yun J.
        • Gu S.M.
        • Yun H.M.
        • Son D.J.
        • Park M.H.
        • Lee M.S.
        • et al.
        Myelin oligodendrocyte glycoprotein (MOG35-55)-induced experimental autoimmune encephalomyelitis is ameliorated in interleukin-32 alpha transgenic mice.
        Oncotarget. 2015; 6: 40452-40463
        • Zhen J.
        • Yuan J.
        • Fu Y.
        • Zhu R.
        • Wang M.
        • Chang H.
        • et al.
        IL-22 promotes Fas expression in oligodendrocytes and inhibits FOXP3 expression in T cells by activating the NF-kappaB pathway in multiple sclerosis.
        Mol. Immunol. 2017; 82: 84-93