Advertisement

Molecular Medicine

, Volume 20, Issue 1, pp 684–696 | Cite as

Role of Glycine N-Methyltransferase in the Regulation of T-Cell Responses in Experimental Autoimmune Encephalomyelitis

  • Chung-Hsien Li
  • Ming-Hong Lin
  • Shih-Han Chu
  • Pang-Hsien Tu
  • Cheng-Chieh Fang
  • Chia-Hung Yen
  • Peir-In Liang
  • Jason C. Huang
  • Yu-Chia Su
  • Huey-Kang Sytwu
  • Yi-Ming Arthur Chen
Research Article

Abstract

Glycine N-methyltransferase (GNMT) is known for its function as a tumor suppressor gene. Since 100% of female Gnmt−/− mice developed hepatocellular carcinoma, we hypothesized that Gnmt−/− mice may have defective immune surveillance. In this study, we examined the immune modulation of GNMT in T-cell responses using experimental autoimmune encephalomyelitis (EAE). The results showed that EAE severity was reduced significantly in Gnmt−/− mice. Pathological examination of the spinal cords revealed that Gnmt−/− mice had significantly lower levels of mononuclear cell infiltration and demyelination than the wild-type mice. In addition, quantitative real-time PCR showed that expression levels of proinflammatory cytokines, including interferon (IFN)-γ and interleukin (IL)-17A, were much lower in the spinal cord of Gnmt−/− than in that of wild-type mice. Accordingly, myelin oligodendrocyte glycoprotein (MOG)-specific T-cell proliferation and induction of T-helper (Th)1 and Th17 cells were markedly suppressed in MOG35–55-induced Gnmt−/− mice. Moreover, the number of regulatory T (Treg) cells was increased significantly in these mice. When the T-cell receptor was stimulated, the proliferative capacity and the activation status of mTOR-associated downstream signaling were decreased significantly in Gnmt−/− CD4+ T cells via an IL-2- and CD25-independent manner. Moreover, GNMT deficiency enhanced the differentiation of Treg cells without affecting the differentiation of Th1 and Th17 cells. Furthermore, the severity of EAE in mice adoptive transferred with GNMT-deficient CD4+ T cells was much milder than in those with wild-type CD4+ T cells. In summary, our findings suggest that GNMT is involved in the pathogenesis of EAE and plays a crucial role in the regulation of CD4+ T-cell functions.

Notes

Acknowledgments

This study was supported partially by Kaohsiung Medical University Aim for the Top Universities Grant, KMU-TP103E00 and KMU-TP103E09; Aim for the Top 500 Universities Grant, DT103009; NSYSU-KMU JOINT RESEARCH PROJECT, NSYSUKMU103-I010; Progam to Upgrade the R&D Capabilities of Private Universities Grant, MOST103-2632-B-037-001; and Health and Welfare Surcharge of Tobacco Products, Ministry of Health and Welfare Grant, MOHW103-TD-B-111-05. We thank Chuen-Miin Leu for providing reagents, Marcelo Chen for revising the English writing and the staff from the Center of Infectious Disease and Cancer Research (CICAR) of Kaohsiung Medical University for technical assistance.

Supplementary material

10020_2014_2001684_MOESM1_ESM.pdf (2 mb)
Supplementary material, approximately 2.03 MB.

References

  1. 1.
    Ogawa H, Fujioka M. (1982) Purification and properties of glycine N-methyltransferase from rat liver. J. Biol. Chem. 257:3447–52.PubMedGoogle Scholar
  2. 2.
    Cook RJ, Wagner C. (1984) Glycine N-methyltransferase is a folate binding protein of rat liver cytosol. Proc. Natl. Acad. Sci. U. S. A. 81:3631–4.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Chen SY, et al. (2004) Glycine N-methyltransferase tumor susceptibility gene in the benzo(a)pyrene-detoxification pathway. Cancer Res. 64:3617–23.CrossRefPubMedGoogle Scholar
  4. 4.
    Yen CH, et al. (2009) Glycine N-methyltransferase affects the metabolism of aflatoxin B1 and blocks its carcinogenic effect. Toxicol. Appl. Pharmacol. 235:296–304.CrossRefPubMedGoogle Scholar
  5. 5.
    Yen CH, et al. (2012) Functional characterization of glycine N-methyltransferase and its interactive protein DEPDC6/DEPTOR in hepatocellular carcinoma. Mol. Med. 18:286–96.CrossRefPubMedGoogle Scholar
  6. 6.
    Liao YJ, et al. (2012) Glycine N-methyltransferase deficiency affects Niemann-Pick type C2 protein stability and regulates hepatic cholesterol homeostasis. Mol. Med. 18:412–22.PubMedGoogle Scholar
  7. 7.
    Chen YM, et al. (1998) Characterization of glycine-N-methyltransferase-gene expression in human hepatocellular carcinoma. Int. J. Cancer. 75:787–93.CrossRefPubMedGoogle Scholar
  8. 8.
    Liu HH, et al. (2003) Characterization of reduced expression of glycine N-methyltransferase in cancerous hepatic tissues using two newly developed monoclonal antibodies. J. Biomed. Sci. 10:87–97.CrossRefPubMedGoogle Scholar
  9. 9.
    Liao YJ, et al. (2009) Characterization of a glycine N-methyltransferase gene knockout mouse model for hepatocellular carcinoma: Implications of the gender disparity in liver cancer susceptibility. Int. J. Cancer. 124:816–26.CrossRefPubMedGoogle Scholar
  10. 10.
    Liu SP, et al. (2007) Glycine N-methyltransferase−/− mice develop chronic hepatitis and glycogen storage disease in the liver. Hepatology. 46:1413–25.CrossRefPubMedGoogle Scholar
  11. 11.
    Chen CY, et al. (2012) Deficiency of glycine N-methyltransferase aggravates atherosclerosis in apolipoprotein E-null mice. Mol. Med. 18:744–52.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Chou WY, et al. (2014) Role of glycine N-methyltransferase in experimental ulcerative colitis. J. Gastroenterol. Hepatol. 29:494–501.CrossRefPubMedGoogle Scholar
  13. 13.
    Gomez-Santos L, et al. (2012) Inhibition of natural killer cells protects the liver against acute injury in the absence of glycine N-methyltransferase. Hepatology. 56:747–59.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    McFarland HF, Martin R. (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat. Immunol. 8:913–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Bottiglieri T, Hyland K, Reynolds EH. (1994) The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs. 48:137–52.CrossRefPubMedGoogle Scholar
  16. 16.
    Hyland K, et al. (1988) Demyelination and decreased S-adenosylmethionine in 5,10-methylenetetrahydrofolate reductase deficiency. Neurology. 38:459–62.CrossRefPubMedGoogle Scholar
  17. 17.
    Metz J. (1992) Cobalamin deficiency and the pathogenesis of nervous system disease. Annu. Rev. Nutr. 12:59–79.CrossRefPubMedGoogle Scholar
  18. 18.
    Friese MA, Jensen LT, Willcox N, Fugger L. (2006) Humanized mouse models for organ-specific autoimmune diseases. Curr. Opin. Immunol. 18:704–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Bettelli E, et al. (2004) Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J. Exp. Med. 200:79–87.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ivanov, II, et al. (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 126:1121–33.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Murphy AC, Lalor SJ, Lynch MA, Mills KH. (2010) Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav. Immun. 24:641–51.CrossRefPubMedGoogle Scholar
  22. 22.
    Stromnes IM, Goverman JM. (2006) Active induction of experimental allergic encephalomyelitis. Nat. Protoc. 1:1810–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Li H, Nourbakhsh B, Ciric B, Zhang GX, Rostami A. (2010) Neutralization of IL-9 ameliorates experimental autoimmune encephalomyelitis by decreasing the effector T cell population. J. Immunol. 185:4095–100.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lin MH, et al. (2014) T cell-specific BLIMP-1 deficiency exacerbates experimental autoimmune encephalomyelitis in nonobese diabetic mice by increasing Th1 and Th17 cells. Clin. Immunol. 151:101–13.CrossRefPubMedGoogle Scholar
  25. 25.
    El-behi M, Rostami A, Ciric B. (2010) Current views on the roles of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. J. Neuroimmune. Pharmacol. 5:189–97.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kuchroo VK, et al. (2002) T cell response in experimental autoimmune encephalomyelitis (EAE): role of self and cross-reactive antigens in shaping, tuning, and regulating the autopathogenic T cell repertoire. Annu. Rev. Immunol. 20:101–23.CrossRefPubMedGoogle Scholar
  27. 27.
    Bonnevier JL, Yarke CA, Mueller DL. (2006) Sustained B7/CD28 interactions and resultant phosphatidylinositol 3-kinase activity maintain G1—>S phase transitions at an optimal rate. Eur. J. Immunol. 36:1583–97.Google Scholar
  28. 28.
    Lucas PJ, Negishi I, Nakayama K, Fields LE, Loh DY. (1995) Naive CD28-deficient T cells can initiate but not sustain an in vitro antigen-specific immune response. J. Immunol. 154:5757–68.PubMedGoogle Scholar
  29. 29.
    Powell JD, Ragheb JA, Kitagawa-Sakakida S, Schwartz RH. (1998) Molecular regulation of interleukin-2 expression by CD28 co-stimulation and anergy. Immunol. Rev. 165:287–300.CrossRefPubMedGoogle Scholar
  30. 30.
    Lin JT, et al. (2009) Naive CD4 T cell proliferation is controlled by mammalian target of rapamycin regulation of GRAIL expression. J. Immunol. 182:5919–28.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Jones RG, Thompson CB. (2007) Revving the engine: signal transduction fuels T cell activation. Immunity. 27:173–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Mondino A, Mueller DL. (2007) mTOR at the crossroads of T cell proliferation and tolerance. Semin. Immunol. 19:162–72.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kumar V, Stellrecht K, Sercarz E. (1996) Inactivation of T cell receptor peptide-specific CD4 regulatory T cells induces chronic experimental autoimmune encephalomyelitis (EAE). J. Exp. Med. 184:1609–17.CrossRefPubMedGoogle Scholar
  34. 34.
    Yen CH, Lin YT, Chen HL, Chen SY, Chen YM. (2013) The multi-functional roles of GNMT in toxicology and cancer. Toxicol. Appl. Pharmacol. 266:67–75.CrossRefPubMedGoogle Scholar
  35. 35.
    Wang YC, Tang FY, Chen SY, Chen YM, Chiang EP. (2011) Glycine-N methyltransferase expression in HepG2 cells is involved in methyl group homeostasis by regulating transmethylation kinetics and DNA methylation. J. Nutr. 141:777–82.CrossRefPubMedGoogle Scholar
  36. 36.
    Glass CK, Witztum JL. (2001) Atherosclerosis. the road ahead. Cell. 104:503–16.CrossRefGoogle Scholar
  37. 37.
    Bernotiene E, Palmer G, Gabay C. (2006) The role of leptin in innate and adaptive immune responses. Arthritis Res. Ther. 8:217.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Yuan CS, Saso Y, Lazarides E, Borchardt RT, Robins MJ. (1999) Recent advances in S-adenosyl-L-homocysteine hydrolase inhibitors and their potential clinical applications. Expert Opin. Ther. Pat. 9:1197–206.CrossRefGoogle Scholar
  39. 39.
    De La Haba G, Cantoni GL. (1959) The enzymatic synthesis of S-adenosyl-L-homocysteine from adenosine and homocysteine. J. Biol. Chem. 234:603–8.Google Scholar
  40. 40.
    Wu QL, et al. (2005) Inhibition of S-adenosyl-L-homocysteine hydrolase induces immunosuppression. J. Pharmacol. Exp. Ther. 313:705–11.CrossRefPubMedGoogle Scholar
  41. 41.
    Jurgensen CH, Wolberg G, Zimmerman TP. (1989) Inhibition of neutrophil adherence to endothelial cells by 3-deazaadenosine. Agents Actions. 27:398–400.CrossRefPubMedGoogle Scholar
  42. 42.
    Lawson BR, et al. (2007) Inhibition of transmethylation down-regulates CD4 T cell activation and curtails development of autoimmunity in a model system. J. Immunol. 178:5366–74.CrossRefPubMedGoogle Scholar
  43. 43.
    Fu YF, et al. (2006) A reversible S-adenosyl-L-homocysteine hydrolase inhibitor ameliorates experimental autoimmune encephalomyelitis by inhibiting T cell activation. J. Pharmacol. Exp. Ther. 319:799–808.CrossRefPubMedGoogle Scholar
  44. 44.
    Dinn JJ, et al. (1980) Methyl group deficiency in nerve tissue: a hypothesis to explain the lesion of subacute combined degeneration. Ir. J. Med. Sci. 149:1–4.CrossRefPubMedGoogle Scholar
  45. 45.
    Kim S, Lim IK, Park GH, Paik WK. (1997) Biological methylation of myelin basic protein: enzymology and biological significance. Int. J. Biochem. Cell Biol. 29:743–51.CrossRefPubMedGoogle Scholar
  46. 46.
    Smith-Garvin JE, Koretzky GA, Jordan MS. (2009) T cell activation. Annu. Rev. Immunol. 27:591–619.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Delgoffe GM, et al. (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 30:832–44.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Delgoffe GM, et al. (2011) The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12:295–303.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Colombetti S, Basso V, Mueller DL, Mondino A. (2006) Prolonged TCR/CD28 engagement drives IL-2-independent T cell clonal expansion through signaling mediated by the mammalian target of rapamycin. J. Immunol. 176:2730–8.CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2014

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • Chung-Hsien Li
    • 1
    • 2
  • Ming-Hong Lin
    • 3
  • Shih-Han Chu
    • 1
    • 2
  • Pang-Hsien Tu
    • 4
  • Cheng-Chieh Fang
    • 1
    • 2
  • Chia-Hung Yen
    • 2
    • 5
  • Peir-In Liang
    • 6
  • Jason C. Huang
    • 7
  • Yu-Chia Su
    • 8
  • Huey-Kang Sytwu
    • 3
  • Yi-Ming Arthur Chen
    • 2
    • 9
    • 10
    • 11
  1. 1.Institute of Microbiology and ImmunologyNational Yang-Ming UniversityTaipeiTaiwan
  2. 2.Center for Infectious Disease and Cancer Research (CICAR)Kaohsiung Medical UniversityKaohsiung CityTaiwan
  3. 3.Department and Graduate Institute of Microbiology and ImmunologyNational Defense Medical CenterTaipeiTaiwan
  4. 4.Institute of Biomedical SciencesAcademia SinicaTaipeiTaiwan
  5. 5.Graduate Institute of Natural Products, College of PharmacyKaohsiung Medical UniversityKaohsiungTaiwan
  6. 6.Department of Pathology, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiungTaiwan
  7. 7.Department of Biotechnology and Laboratory Science in MedicineNational Yang-Ming UniversityTaipeiTaiwan
  8. 8.National Applied Research LaboratoriesNational Laboratory Animal CenterTaipeiTaiwan
  9. 9.Institute of Biomedical SciencesNational Sun Yat-sen UniversityKaohsiungTaiwan
  10. 10.Department of Microbiology and Immunology, Institute of Medical Research and Institute of Clinical Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  11. 11.Kaohsiung CityTaiwan

Personalised recommendations