nach oben

Erschienen in:

26.02.2019 | ORIGINAL ARTICLE

Silymarin Restores Regulatory T Cells (Tregs) Function in Multiple Sclerosis (MS) Patients In Vitro

verfasst von: Maryam Shariati, Vahid Shaygannejad, Faezeh Abbasirad, Fahimeh Hosseininasab, Mohammad Kazemi, Omid Mirmosayyeb, Nafiseh Esmaeil

Erschienen in: Inflammation | Ausgabe 4/2019

Einloggen, um Zugang zu erhalten

Abstract

Dysregulation of the immune system and impairment in the function and number of patient-derived regulatory T cells (Treg) have an important role in multiple sclerosis (MS) pathogenesis. MS patients still receive different medications to overcome the relapses and to slow the disease progression. However, the benefits of these therapies are limited and are accompanied by different side effects. The immunoregulatory effects of Silymarin as a plant-derived flavonoid have shown in studies. In the present study, regulatory T cells (Tregs) were isolated from MS patients who diagnosed as new cases and IFN-β-treated RRMS patients. Isolated Treg cells were cultured in the presence of different concentrations of Silymarin (50, 100, 150 μM) for 48, 72, and 120 h. Proliferation and activation of Treg cells were assessed by flow cytometry. Also, FOXP3, JAK3, and STAT5 gene expression, IL-10, and TGF-β production by Tregs were evaluated by real-time PCR and ELISA respectively. The results showed that Silymarin promoted Treg proliferation at 100 μM concentration after 72 h. Additionally, IL-10, TGF-β levels, and FOXP3, JAK3, and STAT5 gene expression enhanced by Silymarin dose and time dependently. Our preliminary results suggest that the induction and activation of Tregs could be an underlying mechanism of the ancient used herbal medicine Silymarin, providing effective means against autoimmune and inflammatory diseases.

Danikowski, K.M., S. Jayaraman, and B.S. Prabhakar. 2017. Regulatory T cells in multiple sclerosis and myasthenia gravis. Journal of Neuroinflammation 14 (1): 117. https://doi.org/10.1186/s12974-017-0892-8.CrossRefPubMedPubMedCentral

Lee, M.J., J.H. Choi, S.J. Lee, and I.H. Cho. 2017. Oriental medicine Samhwangsasim-tang alleviates experimental autoimmune encephalomyelitis by suppressing Th1 cell responses and upregulating Treg cell responses. Frontiers in Pharmacology 8: 192. https://doi.org/10.3389/fphar.2017.00192.CrossRefPubMedPubMedCentral

Schloder, J., C. Berges, F. Luessi, and H. Jonuleit. 2017. Dimethyl fumarate therapy significantly improves the responsiveness of T cells in multiple sclerosis patients for immunoregulation by regulatory T cells. International Journal of Molecular Sciences 18 (2). https://doi.org/10.3390/ijms18020271.

George, M.M., K. Subramanian Vignesh, J.A. Landero Figueroa, J.A. Caruso, and G.S. Deepe Jr. 2016. Zinc induces dendritic cell tolerogenic phenotype and skews regulatory T cell-Th17 balance. Journal of Immunology 197 (5): 1864–1876. https://doi.org/10.4049/jimmunol.1600410.CrossRef

Spence, A., J.E. Klementowicz, J.A. Bluestone, and Q. Tang. 2015. Targeting Treg signaling for the treatment of autoimmune diseases. Current Opinion in Immunology 37: 11–20. https://doi.org/10.1016/j.coi.2015.09.002.CrossRefPubMedPubMedCentral

Joller, N., and V.K. Kuchroo. 2014. Good guys gone bad: exTreg cells promote autoimmune arthritis. Nature Medicine 20 (1): 15–17. https://doi.org/10.1038/nm.3439.CrossRefPubMed

Nie, J., Y.Y. Li, S.G. Zheng, A. Tsun, and B. Li. 2015. FOXP3(+) Treg cells and gender bias in autoimmune diseases. Frontiers in Immunology 6: 493. https://doi.org/10.3389/fimmu.2015.00493.CrossRefPubMedPubMedCentral

Goldstein, J.D., A. Burlion, B. Zaragoza, K. Sendeyo, J.K. Polansky, J. Huehn, E. Piaggio, B.L. Salomon, and G. Marodon. 2016. Inhibition of the JAK/STAT signaling pathway in regulatory T cells reveals a very dynamic regulation of Foxp3 expression. PLoS One 11 (4): e0153682. https://doi.org/10.1371/journal.pone.0153682.CrossRefPubMedPubMedCentral

Villarino, A.V., Y. Kanno, and J.J. O’Shea. 2017. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nature Immunology 18 (4): 374–384. https://doi.org/10.1038/ni.3691.CrossRefPubMed

10.

Zheng, Y., Z. Wang, L. Deng, G. Zhang, X. Yuan, L. Huang, W. Xu, and L. Shen. 2015. Modulation of STAT3 and STAT5 activity rectifies the imbalance of Th17 and Treg cells in patients with acute coronary syndrome. Clinical Immunology 157 (1): 65–77. https://doi.org/10.1016/j.clim.2014.12.012.CrossRefPubMed

11.

Owen, D.L., and M.A. Farrar. 2017. STAT5 and CD4 (+) T cell immunity. F1000Res 6: 32. https://doi.org/10.12688/f1000research.9838.1.CrossRefPubMedPubMedCentral

12.

Levings, M.K., R. Bacchetta, U. Schulz, and M.G. Roncarolo. 2002. The role of IL-10 and TGF-beta in the differentiation and effector function of T regulatory cells. International Archives of Allergy and Immunology 129 (4): 263–276. https://doi.org/10.1159/000067596.CrossRefPubMed

13.

Chaudhry, A., R.M. Samstein, P. Treuting, Y. Liang, M.C. Pils, J.M. Heinrich, R.S. Jack, F.T. Wunderlich, J.C. Bruning, W. Muller, and A.Y. Rudensky. 2011. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 34 (4): 566–578. https://doi.org/10.1016/j.immuni.2011.03.018.CrossRefPubMedPubMedCentral

14.

Wan, Y.Y., and R.A. Flavell. 2007. Yin-Yang’ functions of transforming growth factor-beta and T regulatory cells in immune regulation. Immunological Reviews 220: 199–213. https://doi.org/10.1111/j.1600-065X.2007.00565.x.CrossRefPubMedPubMedCentral

15.

Mokhtarian, F., Y. Shi, D. Shirazian, L. Morgante, A. Miller, and D. Grob. 1994. Defective production of anti-inflammatory cytokine, TGF-beta by T cell lines of patients with active multiple sclerosis. Journal of Immunology 152 (12): 6003–6010.

16.

Mirshafiey, A., and M. Mohsenzadegan. 2009. TGF-beta as a promising option in the treatment of multiple sclerosis. Neuropharmacology 56 (6–7): 929–936. https://doi.org/10.1016/j.neuropharm.2009.02.007.CrossRefPubMed

17.

Mahdavian, S., U. Dike, A. Bryant, C. Davison, P. Ghazvini, and A. Hill. 2010. Multiple sclerosis: a supplement on the disease state, current therapies, and investigational treatments. Journal of Pharmacy Practice 23 (2): 91–100. https://doi.org/10.1177/0897190009360022.CrossRefPubMed

18.

Axisa, P.P., and D.A. Hafler. 2016. Multiple sclerosis: genetics, biomarkers, treatments. Current Opinion in Neurology 29 (3): 345–353. https://doi.org/10.1097/WCO.0000000000000319.CrossRefPubMed

19.

Landi, D., M. Albanese, F. Buttari, F. Monteleone, L. Boffa, S. Rossi, C. Motta, E. Puma, and D. Centonze. 2017. Management of flu-like syndrome with cetirizine in patients with relapsing-remitting multiple sclerosis during therapy with interferon beta: results of a randomized, cross-over, placebo-controlled pilot study. PLoS One 12 (7): e0165415. https://doi.org/10.1371/journal.pone.0165415.CrossRefPubMedPubMedCentral

20.

Anthony, K.P., and M.A. Saleh. 2013. Free radical scavenging and antioxidant activities of silymarin components. Antioxidants (Basel) 2 (4): 398–407. https://doi.org/10.3390/antiox2040398.CrossRef

21.

Feher, J., and G. Lengyel. 2012. Silymarin in the prevention and treatment of liver diseases and primary liver cancer. Current Pharmaceutical Biotechnology 13 (1): 210–217.CrossRef

22.

Esmaeil, N., S.B. Anaraki, M. Gharagozloo, and B. Moayedi. 2017. Silymarin impacts on immune system as an immunomodulator: one key for many locks. International Immunopharmacology 50: 194–201. https://doi.org/10.1016/j.intimp.2017.06.030.CrossRefPubMed

23.

Sarineh Shajanian, M.G., Mazdak Ganjalikhani-Hakemi, and M. Rafiee. 2015. Comparing in-vitro effects of two immunosuppressive drugs on the expression of Foxp3 from naïve CD4+ T cells. Journal of Isfahan Medical School 33 (329): 457–466.

24.

Sharma, M., S. Sharma, and J. Wadhwa. 2019. Improved uptake and therapeutic intervention of curcumin via designing binary lipid nanoparticulate formulation for oral delivery in inflammatory bowel disorder. Artifical Cells, Nanomedicine, Biotechnology 47 (1): 45–55. https://doi.org/10.1080/21691401.2018.1543191.CrossRef

25.

Manconi, M., M.L. Manca, D. Valenti, E. Escribano, H. Hillaireau, A.M. Fadda, and E. Fattal. 2017. Chitosan and hyaluronan coated liposomes for pulmonary administration of curcumin. International Journal of Pharmaceutics 525 (1): 203–210. https://doi.org/10.1016/j.ijpharm.2017.04.044.CrossRefPubMed

26.

Maria Letizia Manca, J.E.P., Virginia Melis, Donatella Valenti, Maria Cristina Cardia, Donatella Lattuada, Elvira Escribano-Ferrer, Anna Maria Fadda, and Maria Manconia. 2015. Nanoincorporation of curcumin in polymer-glycerosomes and evaluation of their in vitro–in vivo suitability as pulmonary delivery systems. RSC Advances 5 (127): 105149–105159. https://doi.org/10.1039/c5ra24032h.CrossRef

27.

Polman, C.H., S.C. Reingold, B. Banwell, M. Clanet, J.A. Cohen, M. Filippi, K. Fujihara, E. Havrdova, M. Hutchinson, L. Kappos, F.D. Lublin, X. Montalban, P. O’Connor, M. Sandberg-Wollheim, A.J. Thompson, E. Waubant, B. Weinshenker, and J.S. Wolinsky. 2011. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of Neurology 69 (2): 292–302. https://doi.org/10.1002/ana.22366.CrossRefPubMedPubMedCentral

28.

De Maria, R., M.G. Cifone, R. Trotta, M.R. Rippo, C. Festuccia, A. Santoni, and R. Testi. 1994. Triggering of human monocyte activation through CD69, a member of the natural killer cell gene complex family of signal transducing receptors. The Journal of Experimental Medicine 180 (5): 1999–2004.CrossRef

29.

Sancho, D., M. Gomez, and F. Sanchez-Madrid. 2005. CD69 is an immunoregulatory molecule induced following activation. Trends in Immunology 26 (3): 136–140. https://doi.org/10.1016/j.it.2004.12.006.CrossRefPubMed

30.

Cebrian, M., E. Yague, M. Rincon, M. Lopez-Botet, M.O. de Landazuri, and F. Sanchez-Madrid. 1988. Triggering of T cell proliferation through AIM, an activation inducer molecule expressed on activated human lymphocytes. The Journal of Experimental Medicine 168 (5): 1621–1637.CrossRef

31.

Santis, A.G., M.R. Campanero, J.L. Alonso, A. Tugores, M.A. Alonso, E. Yague, J.P. Pivel, and F. Sanchez-Madrid. 1992. Tumor necrosis factor-alpha production induced in T lymphocytes through the AIM/CD69 activation pathway. European Journal of Immunology 22 (5): 1253–1259. https://doi.org/10.1002/eji.1830220521.CrossRefPubMed

32.

Sancho, D., M. Gomez, F. Viedma, E. Esplugues, M. Gordon-Alonso, M.A. Garcia-Lopez, H. de la Fuente, A.C. Martinez, P. Lauzurica, and F. Sanchez-Madrid. 2003. CD69 downregulates autoimmune reactivity through active transforming growth factor-beta production in collagen-induced arthritis. The Journal of Clinical Investigation 112 (6): 872–882. https://doi.org/10.1172/JCI19112.CrossRefPubMedPubMedCentral

33.

Esplugues, E., D. Sancho, J. Vega-Ramos, C. Martinez, U. Syrbe, A. Hamann, P. Engel, F. Sanchez-Madrid, and P. Lauzurica. 2003. Enhanced antitumor immunity in mice deficient in CD69. The Journal of Experimental Medicine 197 (9): 1093–1106. https://doi.org/10.1084/jem.20021337.CrossRefPubMedPubMedCentral

34.

Han, Y., Y. Yang, Z. Chen, Z. Jiang, Y. Gu, Y. Liu, S. Xu, C. Lin, Z. Pan, W. Zhou, and X. Cao. 2014. Human hepatocellular carcinoma-infiltrating CD4(+)CD69(+)Foxp3(-) regulatory T cell suppresses T cell response via membrane-bound TGF-beta1. Journal of Molecular Medicine (Berlin) 92 (5): 539–550. https://doi.org/10.1007/s00109-014-1143-4.CrossRef

35.

Cortes, J.R., R. Sanchez-Diaz, E.R. Bovolenta, O. Barreiro, S. Lasarte, A. Matesanz-Marin, M.L. Toribio, F. Sanchez-Madrid, and P. Martin. 2014. Maintenance of immune tolerance by Foxp3+ regulatory T cells requires CD69 expression. Journal of Autoimmunity 55: 51–62. https://doi.org/10.1016/j.jaut.2014.05.007.CrossRefPubMedPubMedCentral

36.

Kamphuis, E., T. Junt, Z. Waibler, R. Forster, and U. Kalinke. 2006. Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia. Blood 108 (10): 3253–3261. https://doi.org/10.1182/blood-2006-06-027599.CrossRefPubMed

37.

Almasi, E., M. Gharagozloo, N. Eskandari, A. Almasi, and A.M. Sabzghabaee. 2017. Inhibition of apoptosis and proliferation in T cells by immunosuppressive silymarine. Iranian Journal of Allergy, Asthma, and Immunology 16 (2): 107–119.PubMed

38.

Treadaway, K., G. Cutter, A. Salter, S. Lynch, J. Simsarian, J. Corboy, D. Jeffery, B. Cohen, K. Mankowski, J. Guarnaccia, L. Schaeffer, R. Kanter, D. Brandes, C. Kaufman, D. Duncan, E. Marder, A. Allen, J. Harney, J. Cooper, D. Woo, O. Stuve, M. Racke, and E.M. Frohman. 2009. Factors that influence adherence with disease-modifying therapy in MS. Journal of Neurology 256 (4): 568–576. https://doi.org/10.1007/s00415-009-0096-y.CrossRefPubMed

39.

Stromnes, I.M., and J.M. Goverman. 2006. Active induction of experimental allergic encephalomyelitis. Nature Protocols 1 (4): 1810–1819. https://doi.org/10.1038/nprot.2006.285.CrossRefPubMed

40.

Gharagozloo, M., E.N. Javid, A. Rezaei, and K. Mousavizadeh. 2013. Silymarin inhibits cell cycle progression and mTOR activity in activated human T cells: therapeutic implications for autoimmune diseases. Basic & Clinical Pharmacology & Toxicology 112 (4): 251–256. https://doi.org/10.1111/bcpt.12032.CrossRef

41.

Soper, D.M., D.J. Kasprowicz, and S.F. Ziegler. 2007. IL-2Rbeta links IL-2R signaling with Foxp3 expression. European Journal of Immunology 37 (7): 1817–1826. https://doi.org/10.1002/eji.200737101.CrossRefPubMed

42.

Zorn, E., E.A. Nelson, M. Mohseni, F. Porcheray, H. Kim, D. Litsa, R. Bellucci, E. Raderschall, C. Canning, R.J. Soiffer, D.A. Frank, and J. Ritz. 2006. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108 (5): 1571–1579. https://doi.org/10.1182/blood-2006-02-004747.CrossRefPubMedPubMedCentral

43.

Chen, H., L. Zhang, H. Zhang, Y. Xiao, L. Shao, H. Li, H. Yin, R. Wang, G. Liu, D. Corley, Z. Yang, and Y. Zhao. 2013. Disruption of TSC1/2 signaling complex reveals a checkpoint governing thymic CD4+ CD25+ Foxp3+ regulatory T-cell development in mice. The FASEB Journal 27 (10): 3979–3990. https://doi.org/10.1096/fj.13-235408.CrossRefPubMed

44.

Kaur, S., L. Lal, A. Sassano, B. Majchrzak-Kita, M. Srikanth, D.P. Baker, E. Petroulakis, N. Hay, N. Sonenberg, E.N. Fish, and L.C. Platanias. 2007. Regulatory effects of mammalian target of rapamycin-activated pathways in type I and II interferon signaling. The Journal of Biological Chemistry 282 (3): 1757–1768. https://doi.org/10.1074/jbc.M607365200.CrossRefPubMed

45.

Wan, Y.Y., and R.A. Flavell. 2007. Regulatory T cells, transforming growth factor-beta, and immune suppression. Proceedings of the American Thoracic Society 4 (3): 271–276. https://doi.org/10.1513/pats.200701-020AW.CrossRefPubMedPubMedCentral

46.

Zheng, S.G., J.D. Gray, K. Ohtsuka, S. Yamagiwa, and D.A. Horwitz. 2002. Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25- precursors. Journal of Immunology 169 (8): 4183–4189.CrossRef

47.

Chen, W., W. Jin, N. Hardegen, K.J. Lei, L. Li, N. Marinos, G. McGrady, and S.M. Wahl. 2003. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. The Journal of Experimental Medicine 198 (12): 1875–1886. https://doi.org/10.1084/jem.20030152.CrossRefPubMedPubMedCentral

48.

Hou, Y., H. Wang, F. Zhang, F. Sun, M. Xin, M. Li, J. Li, and X. Wu. 2019. Novel self-nanomicellizing solid dispersion based on rebaudioside A: a potential nanoplatform for oral delivery of curcumin. International Journal of Nanomedicine 14: 557–571. https://doi.org/10.2147/IJN.S191337.CrossRefPubMedPubMedCentral

49.

Uchiyama, H., Y. Wada, Y. Hatanaka, Y. Hirata, M. Taniguchi, K. Kadota, and Y. Tozuka. 2019. Solubility and permeability improvement of quercetin by an interaction between alpha-glucosyl stevia nano-aggregates and hydrophilic polymer. Journal of Pharmaceutical Sciences. https://doi.org/10.1016/j.xphs.2019.01.007.

Titel: Silymarin Restores Regulatory T Cells (Tregs) Function in Multiple Sclerosis (MS) Patients In Vitro
verfasst von: Maryam Shariati
Vahid Shaygannejad
Faezeh Abbasirad
Fahimeh Hosseininasab
Mohammad Kazemi
Omid Mirmosayyeb
Nafiseh Esmaeil
Publikationsdatum: 26.02.2019
Verlag: Springer US
Erschienen in: Inflammation / Ausgabe 4/2019
Print ISSN: 0360-3997
Elektronische ISSN: 1573-2576
DOI: https://doi.org/10.1007/s10753-019-00980-9

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

24.04.2024 | DGIM 2024 | Kongressbericht | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Silymarin Restores Regulatory T Cells (Tregs) Function in Multiple Sclerosis (MS) Patients In Vitro

Abstract

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2019

The Deleterious Impact of Interleukin 9 to Hepatorenal Physiology

Amelioration of Lipopolysaccharide-Induced Nephrotic Proteinuria by NFAT5 Depletion Involves Suppressed NF-κB Activity

Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB) Ameliorates the Inflammatory Response in Periodontal Disease

Regulation of KDM2B and Brg1 on Inflammatory Response of Nasal Mucosa in CRSwNP

Formononetin Antagonizes the Interleukin-1β-Induced Catabolic Effects Through Suppressing Inflammation in Primary Rat Chondrocytes

Probucol Ameliorates Complete Freund’s Adjuvant-Induced Hyperalgesia by Targeting Peripheral and Spinal Cord Inflammation

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin