Skip to main content
SpringerLink
Log in
Book cover

Midkine: From Embryogenesis to Pathogenesis and Therapy pp 143–151Cite as

Midkine and Multiple Sclerosis

  • Chapter
  • First Online:

Abstract

Multiple sclerosis (MS) is a neurological autoimmune diseases characterized by inflammatory demyelination with subsequent neuronal degeneration in the central nervous system. Experimental autoimmune encephalomyelitis (EAE) mouse is widely used as an animal model of MS. Both MS and EAE have been considered as autoreactive T-helper type 1 (Th1) and T-helper-17 (Th17) cells-mediated diseases. CD4+CD25+ regulatory T (Treg) cell is a crucial mediator of autoimmune tolerance so that abnormalities in Treg cell function may contribute to the development of autoimmune diseases. However, the factors that regulate Treg cells are largely unknown. We recently showed that deficiency in midkine (MK) attenuated EAE due to an expansion of the Treg cell population as well as a decrease in the numbers of autoreactive Th1 and Th17 cells. MK decreased the Treg cell population by suppression of STAT5 phosphorylation which is essential for the expression of Foxp3, the master transcriptional factor of Treg cell differentiation. Furthermore, pharmacological inhibition of MK by specific RNA aptamer significantly expanded the Treg cell population and alleviated EAE symptoms without detectable adverse effects. Therefore, MK is a critical suppressor of Treg cell expansion, and the inhibition of MK may provide an effective therapeutic strategy against autoimmune diseases including MS.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Hemmer B, Archelos JJ, Hartung HP (2002) New concepts in the immunopathogenesis of multiple sclerosis. Nat Rev Neurosci 3:291–301

    Article  PubMed  CAS  Google Scholar 

  2. Mangan PR, Harrington LE, O’Quinn DB et al (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441:231–234

    Article  PubMed  CAS  Google Scholar 

  3. Bettelli E, Carrier Y, Gao W et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238

    Article  PubMed  CAS  Google Scholar 

  4. Weaver CT, Harrington LE, Mangan PR et al (2006) Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24:677–688

    Article  PubMed  CAS  Google Scholar 

  5. Ivanov II, McKenzie BS, Zhou L et al (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133

    Article  PubMed  CAS  Google Scholar 

  6. Codarri L, Gyulveszi G, Tosevski V et al (2011) ROR gamma drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroin-flammation. Nat Immunol 12:560–567

    Article  PubMed  CAS  Google Scholar 

  7. El-Behi M, Ciric B, Dai H et al (2011) The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol 12:568–575

    Article  PubMed  CAS  Google Scholar 

  8. Sakaguchi S (2004) Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562

    Article  PubMed  CAS  Google Scholar 

  9. Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25  +  CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352

    Article  PubMed  CAS  Google Scholar 

  10. Liu H, Leung BP (2006) CD4  +  CD25+ regulatory T cells in health and disease. Clin Exp Pharmacol Physiol 33:519–524

    Article  PubMed  CAS  Google Scholar 

  11. Baecher-Allan C, Hafler DA (2004) Suppressor T cells in human diseases. J Exp Med 200:273–276

    Article  PubMed  CAS  Google Scholar 

  12. Matarese G, Carrieri PB, La Cava A et al (2005) Leptin increase in multiple sclerosis associates with reduced number of CD4(+) CD25+ regulatory T cells. Proc Natl Acad Sci USA 102:5150–5155

    Article  PubMed  CAS  Google Scholar 

  13. Viglietta V, Baecher-Allan C, Weiner HL et al (2004) Loss of functional suppression by CD4  +  CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 199:971–979

    Article  PubMed  CAS  Google Scholar 

  14. Kohm AP, Carpentier PA, Anger HA et al (2002) Cutting edge: CD4  +  CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol 169:4712–4716

    PubMed  CAS  Google Scholar 

  15. Mills KH (2004) Regulatory T cells: friend or foe in immunity to infection? Nat Rev Immunol 4:841–855

    Article  PubMed  CAS  Google Scholar 

  16. von Herrath MG, Harrison LC (2003) Antigen-induced regulatory T cells in autoimmunity. Nat Rev Immunol 3:223–232

    Article  Google Scholar 

  17. Polanczyk MJ, Carson BD, Subramanian S et al (2004) Cutting edge: estrogen drives expansion of the CD4  +  CD25+ regulatory T cell compartment. J Immunol 173:2227–2230

    PubMed  CAS  Google Scholar 

  18. Reddy J, Illes Z, Zhang X et al (2004) Myelin proteolipid protein-specific CD4  +  CD25+ regulatory cells mediate genetic resistance to experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 101:15434–15439

    Article  PubMed  CAS  Google Scholar 

  19. Polanczyk MJ, Hopke C, Huan J et al (2005) Enhanced FoxP3 expression and Treg cell function in pregnant and estrogen-treated mice. J Neuroimmunol 170:85–92

    Article  PubMed  CAS  Google Scholar 

  20. Reddy J, Waldner H, Zhang X et al (2005) Cutting edge: CD4  +  CD25+ regulatory T cells contribute to gender differences in susceptibility to experimental autoimmune encephalomyelitis. J Immunol 175:5591–5595

    PubMed  CAS  Google Scholar 

  21. Fernandez-Martin A, Gonzalez-Rey E, Chorny A et al (2006) Vasoactive intestinal peptide induces regulatory T cells during experimental autoimmune encephalomyelitis. Eur J Immunol 36:318–326

    Article  PubMed  CAS  Google Scholar 

  22. Gonzalez-Rey E, Fernandez-Martin A, Chorny A et al (2006) Therapeutic effect of vasoactive intestinal peptide on experimental autoimmune encephalomyelitis: down-regulation of inflammatory and autoimmune responses. Am J Pathol 168:1179–1188

    Article  PubMed  CAS  Google Scholar 

  23. Beyersdorf N, Gaupp S, Balbach K et al (2005) Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis. J Exp Med 202:445–455

    Article  PubMed  CAS  Google Scholar 

  24. Beyersdorf N, Hanke T, Kerkau T et al (2006) CD28 superagonists put a break on autoimmunity by preferentially activating CD4  +  CD25+ regulatory T cells. Autoimmun Rev 5:40–45

    Article  PubMed  Google Scholar 

  25. Suntharalingam G, Perry MR, Ward S et al (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018–1028

    Article  PubMed  CAS  Google Scholar 

  26. Burchill MA, Yang J, Vogtenhuber C et al (2007) IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol 178:280–290

    PubMed  CAS  Google Scholar 

  27. Yao Z, Kanno Y, Kerenyi M et al (2007) Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109:4368–4375

    Article  PubMed  CAS  Google Scholar 

  28. Muramatsu T (2002) Midkine and pleiotrophin: two related proteins involved in development, survival, inflammation and tumorigenesis. J Biochem (Tokyo) 132:359–371

    Article  CAS  Google Scholar 

  29. Liu X, Mashour GA, Webster HF et al (1998) Basic FGF and FGF receptor 1 are expressed in microglia during experimental autoimmune encephalomyelitis: temporally distinct expression of midkine and pleiotrophin. Glia 24:390–397

    Article  PubMed  CAS  Google Scholar 

  30. Sato W, Kadomatsu K, Yuzawa Y et al (2001) Midkine is involved in neutrophil infiltration into the tubulointerstitium in ischemic renal injury. J Immunol 167:3463–3469

    PubMed  CAS  Google Scholar 

  31. Horiba M, Kadomatsu K, Nakamura E et al (2000) Neointima formation in a restenosis model is suppressed in midkine-deficient mice. J Clin Invest 105:489–495

    Article  PubMed  CAS  Google Scholar 

  32. Maruyama K, Muramatsu H, Ishiguro N et al (2004) Midkine, a heparin-binding growth factor, is fundamentally involved in the pathogenesis of rheumatoid arthritis. Arthritis Rheum 50:1420–1429

    Article  PubMed  CAS  Google Scholar 

  33. Wang J, Takeuchi H, Sonobe Y et al (2008) Inhibition of midkine alleviates experimental autoimmune encephalomyelitis through the expansion of regulatory T cell population. Proc Natl Acad Sci USA 105:3915–3920

    Article  PubMed  CAS  Google Scholar 

  34. Yu CL, Jin YJ, Burakoff SJ (2000) Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation. J Biol Chem 275:599–604

    Article  PubMed  CAS  Google Scholar 

  35. Wilson DS, Szostak JW (1999) In vitro selection of functional nucleic acids. Annu Rev Biochem 68:611–647

    Article  PubMed  CAS  Google Scholar 

  36. Brody EN, Gold L (2000) Aptamers as therapeutic and diagnostic agents. J Biotechnol 74:5–13

    PubMed  CAS  Google Scholar 

  37. Mori T, Oguro A, Ohtsu T et al (2004) RNA aptamers selected against the receptor activator of NF-kappaB acquire general affinity to proteins of the tumor necrosis factor receptor family. Nucleic Acids Res 32:6120–6128

    Article  PubMed  CAS  Google Scholar 

  38. Que-Gewirth NS, Sullenger BA (2007) Gene therapy progress and prospects: RNA aptamers. Gene Ther 14:283–291

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan

    Hideyuki Takeuchi

Authors
  1. Hideyuki Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hideyuki Takeuchi .

Editor information

Editors and Affiliations

  1. Faculty of Medicine, Faculty of Biochemistry, Yeni Yüzyıl University, Yilanli Ayazma 26, Istanbul, 34000, Istanbul, Turkey

    Mine Ergüven

  2. , Department of Health Science, Aichi Gakuin University, 12 Araike, Iwasakicho, Nisshin, Aichi, Japan

    Takashi Muramatsu

  3. , Department of Histology and Embryology, Istanbul University Faculty of Medicine, Millet, Istanbul, Turkey

    Ayhan Bilir

Additional information

Funding: This work was supported in part by a Neuroimmunological Disease Research Committee grant from the Ministry of Health, Labour and Welfare of Japan; a grant-in aid for young scientists; a grant-in-aid for a twenty-first Century Center of Excellence (COE) program from the Ministry of Education, Culture, Sports, Science and Technology of Japan; a Collaborative Development of Innovative Seeds grant; a Core Research for Evolution Science and Technology (CREST) grant from the Japan Science and Technology Agency; and a grant-in-aid for the RNA Information Network from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Conflicts of Interest: I declare no conflicts of interest associated with the present study.

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Takeuchi, H. (2012). Midkine and Multiple Sclerosis. In: Ergüven, M., Muramatsu, T., Bilir, A. (eds) Midkine: From Embryogenesis to Pathogenesis and Therapy. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4234-5_12

Download citation

Publish with us

Policies and ethics

Search

Navigation