Neurological Sciences

, Volume 35, Issue 7, pp 1121–1125 | Cite as

Monomethylfumarate reduces in vitro migration of mononuclear cells

  • T. Dehmel
  • M. Döbert
  • S. Pankratz
  • V. I. Leussink
  • H.-P. Hartung
  • H. Wiendl
  • B. C. Kieseier
Original Article

Abstract

Migration of immunocompetent cells into the central nervous system represents a key event in the immunopathogenesis of multiple sclerosis (MS). Fumaric acid esters have recently been approved for patients with MS. Their mode of action is not fully understood so far. We analyzed the effect of monomethylfumarate (MMF), the immediate metabolite of dimethylfumarate, on migration of lymphocytes and macrophages. Peripheral blood mononuclear cells (PBMCs) were isolated from patients with MS and healthy donors. PBMCs were treated with MMF in vitro and their migratory capacity was studied in a Boyden chamber assay. In addition, expression of matrix metalloproteinases (MMPs), chemokine receptors, adhesion molecules, and molecules of the oxidative stress cascade was assessed. MMF decreased the migratory capacity of T lymphocytes, but not of macrophages. Lymphocytes as well as macrophages responded to MMF by the upregulation of oxidative stress molecules; however, no effect was seen on the expression of MMPs, chemokine receptors, and adhesion molecules. There was no difference in comparison with cells from healthy controls. MMF reduces the migratory activity of lymphocytes most likely by changing their activational state. This points to a potential novel mode of action differentiating this drug from other available immunotherapies.

Keywords

Diemethylfumarate Multiple sclerosis Mode of action Therapy Blood–brain barrier Chemokines Fumaric acid Matrix metalloproteinases 

Notes

Acknowledgments

The authors thank Tatjana Males for technical assistance.

Conflict of interest

None.

References

  1. 1.
    Compston A, Coles A (2002) Multiple sclerosis. Lancet 359:1221–1231PubMedCrossRefGoogle Scholar
  2. 2.
    McFarland HF, Martin R (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 8:913–919PubMedCrossRefGoogle Scholar
  3. 3.
    Schilling S, Goelz S, Linker R, Luehder F, Gold R (2006) Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin Exp Immunol 145:101–107PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Peng H, Gzerau-de-Arellano M, Mehta VB et al (2012) Dimethyl fumarate inhibits dendritic cell maturation via nuclear Factor кB (NF-кB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress activated kinase 1 (MSK1) signaling. J Biol Chem 287:28017–28026PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Linker RA, Lee DH, Ryan S et al (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134:678–692PubMedCrossRefGoogle Scholar
  6. 6.
    Gold R, Kappos L, Arnold DL et al (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367:1098–1107PubMedCrossRefGoogle Scholar
  7. 7.
    Fox RJ, Miller DH, Phillips JT et al (2012) Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 367:1087–1097PubMedCrossRefGoogle Scholar
  8. 8.
    Kopadze T, Dehmel T, Hartung HP et al (2006) Inhibition by mitoxantrone of in vitro migration of immunocompetent cells: a possible mechanism for therapeutic efficacy in the treatment of multiple sclerosis. Arch Neurol 63:1572–1578PubMedCrossRefGoogle Scholar
  9. 9.
    Treumer F, Zhu K, Glaser R, Mrowietz U (2003) Dimethylfumarate is a potent inducer of apoptosis in human T cells. J Invest Dermatol 121:1383–1388PubMedCrossRefGoogle Scholar
  10. 10.
    Dehmel T, Janke A, Hartung HP et al (2007) The cell-specific expression of metalloproteinase-disintegrins (ADAMs) in inflammatory myopathies. Neurobiol Dis 25:665–674PubMedCrossRefGoogle Scholar
  11. 11.
    Stuve O, Dooley NP, Uhm JH et al (1996) Interferon beta-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9. Ann Neurol 40:853–863PubMedCrossRefGoogle Scholar
  12. 12.
    Moharregh-Khiabani D, Blank A, Skripuletz T et al (2010) Effects of fumaric acids on cuprizone induced central nervous system de- and remyelination in the mouse. PLoS One 5:e11769PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Yamazoe Y, Tsubaki M, Matsuoka H et al (2009) Dimethylfumarate inhibits tumor cell invasion and metastasis by suppressing the expression and activities of matrix metalloproteinases in melanoma cells. Cell Biol Int 33:1087–1094PubMedCrossRefGoogle Scholar
  14. 14.
    Wallbrecht K, Drick N, Hund AC, Schön MP (2011) Downregulation of endothelial adhesion molecules by dimethylfumarate, but not monomethylfumarate, and impairment of dynamic lymphocyte–endothelial cell interactions. Exp Dermatol 20:980–985PubMedCrossRefGoogle Scholar
  15. 15.
    Rachakonda G, Sekhar KR, Jowhar D et al (2010) Increased cell migration and plasticity in Nrf2-deficient cancer cell lines. Oncogene 29:3703–3714PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2014

Authors and Affiliations

  • T. Dehmel
    • 1
  • M. Döbert
    • 1
  • S. Pankratz
    • 2
  • V. I. Leussink
    • 1
  • H.-P. Hartung
    • 1
  • H. Wiendl
    • 2
  • B. C. Kieseier
    • 1
  1. 1.Department of Neurology, Medical Faculty, Research Group for Clinical and Experimental NeuroimmunologyHeinrich-Heine UniversityDüsseldorfGermany
  2. 2.Department of NeurologyWestfälische Wilhelms-UniversityMünsterGermany

Personalised recommendations