Skip to main content

Matrine suppresses expression of adhesion molecules and chemokines as a mechanism underlying its therapeutic effect in CNS autoimmunity

Immunologic Research volume 56, pages 189–196 (2013)Cite this article

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a classical experimental model of multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS). Previous reports have suggested that matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, could inhibit clinical EAE, but its mechanism of action is not clear. Our present study showed that MAT treatment resulted in dose-dependent reduction in neurological scores. Consistent with this observation, infiltration of inflammatory cells and demyelination in the CNS were also significantly suppressed. We further studied the mechanism underlying these effects of MAT by determining whether this treatment influences expression of molecules that are involved in the activation and migration of inflammatory cells. Our results showed that MAT significantly inhibited expression and production in the CNS of ICAM-1 and VCAM-1, key adhesive molecules, and CCL3 and CCL5, key chemokines, that attract inflammatory cells into the CNS. Furthermore, the TLR4/MD2 pathway, which plays an important role in the induction of Th1/Th17 cells in EAE, was also significantly inhibited. Together, our study not only demonstrates that MAT may be a novel therapeutic option for the treatment for MS, but also provides further information on mechanisms underlying the effect of MAT treatment.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Popescu BF, Lucchinetti CF. Pathology of demyelinating diseases. Annu Rev Pathol. 2012;7:185–217. doi:10.1146/annurev-pathol-011811-132443.

    PubMed  Article  CAS  Google Scholar 

  2. Kawakami N, Bartholomaus I, Pesic M, Mues M. An autoimmunity odyssey: how autoreactive T cells infiltrate into the CNS. Immunol Rev. 2012;248(1):140–55. doi:10.1111/j.1600-065X.2012.01133.x.

    PubMed  Article  CAS  Google Scholar 

  3. Saidha S, Eckstein C, Calabresi PA. New and emerging disease modifying therapies for multiple sclerosis. Ann N Y Acad Sci. 2012;1247:117–37. doi:10.1111/j.1749-6632.2011.06272.x.

    PubMed  Article  CAS  Google Scholar 

  4. Dore-Duffy P, Washington R, Dragovic L. Expression of endothelial cell activation antigens in microvessels from patients with multiple sclerosis. Adv Exp Med Biol. 1993;331:243–8.

    PubMed  Article  CAS  Google Scholar 

  5. Holman DW, Klein RS, Ransohoff RM. The blood-brain barrier, chemokines and multiple sclerosis. Biochim Biophys Acta. 2011;1812(2):220–30. doi:10.1016/j.bbadis.2010.07.019.

    PubMed  Article  CAS  Google Scholar 

  6. Segal BM. CNS chemokines, cytokines, and dendritic cells in autoimmune demyelination. J Neurol Sci. 2005;228(2):210–4. doi:10.1016/j.jns.2004.10.014.

    PubMed  Article  CAS  Google Scholar 

  7. Sorensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest. 1999;103(6):807–15. doi:10.1172/JCI5150.

    PubMed  Article  CAS  Google Scholar 

  8. Yang J, Yan Y, Ma CG, Kang T, Zhang N, Gran B, et al. Accelerated and enhanced effect of CCR5-transduced bone marrow neural stem cells on autoimmune encephalomyelitis. Acta Neuropathol. 2012;124(4):491–503. doi:10.1007/s00401-012-0989-1.

    PubMed  Article  CAS  Google Scholar 

  9. Bromley SK, Mempel TR, Luster AD. Orchestrating the orchestrators: chemokines in control of T cell traffic. Nat Immunol. 2008;9(9):970–80. doi:10.1038/ni.f.213.

    PubMed  Article  CAS  Google Scholar 

  10. Zhang GX, Baker CM, Kolson DL, Rostami AM. Chemokines and chemokine receptors in the pathogenesis of multiple sclerosis. Mult Scler. 2000;6(1):3–13.

    PubMed  CAS  Google Scholar 

  11. Hla T, Oo ML. Ramping up RANTES in the acute response to arterial injury. J Clin Invest. 2010;120(1):90–2. doi:10.1172/JCI41738.

    PubMed  Article  CAS  Google Scholar 

  12. Christiansen D, Brekke OL, Stenvik J, Lambris JD, Espevik T, Mollnes TE. Differential effect of inhibiting MD-2 and CD14 on LPS- versus whole E. coli bacteria-induced cytokine responses in human blood. Adv Exp Med Biol. 2012;946:237–51. doi:10.1007/978-1-4614-0106-3_14.

    PubMed  Article  CAS  Google Scholar 

  13. Reynolds JM, Martinez GJ, Chung Y, Dong C. Toll-like receptor 4 signaling in T cells promotes autoimmune inflammation. Proc Natl Acad Sci USA. 2012;109(32):13064–9. doi:10.1073/pnas.1120585109.

    PubMed  Article  CAS  Google Scholar 

  14. Li T, Wong VK, Yi XQ, Wong YF, Zhou H, Liu L. Matrine induces cell anergy in human Jurkat T cells through modulation of mitogen-activated protein kinases and nuclear factor of activated T-cells signaling with concomitant up-regulation of anergy-associated genes expression. Biol Pharm Bull. 2010;33(1):40–6.

    PubMed  Article  CAS  Google Scholar 

  15. Zhang Y, Wang S, Li Y, Xiao Z, Hu Z, Zhang J. Sophocarpine and matrine inhibit the production of TNF-alpha and IL-6 in murine macrophages and prevent cachexia-related symptoms induced by colon26 adenocarcinoma in mice. Int Immunopharmacol. 2008;8(13–14):1767–72. doi:10.1016/j.intimp.2008.08.008.

    PubMed  Article  CAS  Google Scholar 

  16. Zhou Y, Wang H, Liang L, Zhao WC, Chen Y, Deng HZ. Total alkaloids of Sophora alopecuroides increases the expression of CD4+ CD25+ Tregs and IL-10 in rats with experimental colitis. Am J Chin Med. 2010;38(2):265–77.

    PubMed  Article  CAS  Google Scholar 

  17. Zhao X, Kan Q, Zhu L, Zhang GX. Matrine suppresses production of IL-23/IL-17 and ameliorates experimental autoimmune encephalomyelitis. Am J Chin Med. 2011;39(5):933–41. doi:10.1142/S0192415X11009317.

    PubMed  Article  CAS  Google Scholar 

  18. Ozugurlu F, Sahin S, Idiz N, Akyol O, Ilhan A, Yigitoglu R, et al. The effect of Nigella sativa oil against experimental allergic encephalomyelitis via nitric oxide and other oxidative stress parameters. Cell Mol Biol (Noisy-le-grand). 2005;51(3):337–42.

    CAS  Google Scholar 

  19. Merkler D, Ernsting T, Kerschensteiner M, Bruck W, Stadelmann C. A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination. Brain. 2006;129(Pt 8):1972–83. doi:10.1093/brain/awl135.

    PubMed  Article  Google Scholar 

  20. Bullard DC, Hu X, Schoeb TR, Collins RG, Beaudet AL, Barnum SR. Intercellular adhesion molecule-1 expression is required on multiple cell types for the development of experimental autoimmune encephalomyelitis. J Immunol. 2007;178(2):851–7.

    PubMed  CAS  Google Scholar 

  21. Engelhardt B. Molecular mechanisms involved in T cell migration across the blood-brain barrier. J Neural Transm. 2006;113(4):477–85. doi:10.1007/s00702-005-0409-y.

    PubMed  Article  CAS  Google Scholar 

  22. Sharief MK, Noori MA, Ciardi M, Cirelli A, Thompson EJ. Increased levels of circulating ICAM-1 in serum and cerebrospinal fluid of patients with active multiple sclerosis. Correlation with TNF-alpha and blood-brain barrier damage. J Neuroimmunol. 1993;43(1–2):15–21.

    PubMed  Article  CAS  Google Scholar 

  23. Rieckmann P, Nunke K, Burchhardt M, Albrecht M, Wiltfang J, Ulrich M, et al. Soluble intercellular adhesion molecule-1 in cerebrospinal fluid: an indicator for the inflammatory impairment of the blood-cerebrospinal fluid barrier. J Neuroimmunol. 1993;47(2):133–40.

    PubMed  Article  CAS  Google Scholar 

  24. Huang D, Han Y, Rani MR, Glabinski A, Trebst C, Sorensen T, et al. Chemokines and chemokine receptors in inflammation of the nervous system: manifold roles and exquisite regulation. Immunol Rev. 2000;177:52–67.

    PubMed  Article  CAS  Google Scholar 

  25. Karpus WJ, Kennedy KJ. MIP-1alpha and MCP-1 differentially regulate acute and relapsing autoimmune encephalomyelitis as well as Th1/Th2 lymphocyte differentiation. J Leukoc Biol. 1997;62(5):681–7.

    PubMed  CAS  Google Scholar 

  26. Liu L, Huang D, Matsui M, He TT, Hu T, Demartino J, et al. Severe disease, unaltered leukocyte migration, and reduced IFN-gamma production in CXCR3−/− mice with experimental autoimmune encephalomyelitis. J Immunol. 2006;176(7):4399–409.

    PubMed  CAS  Google Scholar 

  27. Mellanby RJ, Cambrook H, Turner DG, O'Connor RA, Leech MD, Kurschus FC, et al. TLR-4 ligation of dendritic cells is sufficient to drive pathogenic T cell function in experimental autoimmune encephalomyelitis. J Neuroinflamm. 2012;9:248. doi:10.1186/1742-2094-9-248.

    Article  CAS  Google Scholar 

  28. Hou SW, Liu CY, Li YH, Yu JZ, Feng L, Liu YT, et al. Fasudil ameliorates disease progression in experimental autoimmune encephalomyelitis, acting possibly through antiinflammatory effect. CNS Neurosci Ther. 2012;18(11):909–17. doi:10.1111/cns.12002.

    PubMed  Article  CAS  Google Scholar 

  29. Tang H, Pang S, Wang M, Xiao X, Rong Y, Wang H, et al. TLR4 activation is required for IL-17-induced multiple tissue inflammation and wasting in mice. J Immunol. 2010;185(4):2563–9. doi:10.4049/jimmunol.0903664.

    PubMed  Article  CAS  Google Scholar 

  30. Mao YM, Zeng MD, Lu LG, Wan MB, Li CZ, Chen CW, et al. Capsule oxymatrine in treatment of hepatic fibrosis due to chronic viral hepatitis: a randomized, double blind, placebo-controlled, multicenter clinical study. World J Gastroenterol. 2004;10(22):3269–73.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the Experimental Animal Center of Henan, China. We thank Katherine Regan for editorial assistance and Zichen Li for technical help.

Author information

Affiliations

  1. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China

    Quan-Cheng Kan, Lin Zhu, Nan Liu & Guang-Xian Zhang

  2. Department of Neurology, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Guang-Xian Zhang

Authors
  1. Quan-Cheng Kan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lin Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guang-Xian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Lin Zhu or Guang-Xian Zhang.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kan, QC., Zhu, L., Liu, N. et al. Matrine suppresses expression of adhesion molecules and chemokines as a mechanism underlying its therapeutic effect in CNS autoimmunity. Immunol Res 56, 189–196 (2013). https://doi.org/10.1007/s12026-013-8393-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-013-8393-z

Keywords

  • Matrine
  • Experimental autoimmune encephalomyelitis
  • Adhesion molecules
  • Chemokines