Skip to main content
SpringerLink
Log in

Immunoregulatory effects of vitamin D3 in experimentally induced type 1 diabetes

  • Published:
Cytology and Genetics Aims and scope Submit manuscript

Abstract

The mechanism underlying the impairment of the function of the cellular component of the immune response and its regulation by vitamin D3 in diabetes mellitus remains incompletely characterized. The present study addresses the specific features of the functioning of the T-cell link of immune response and the humoral response to injecyion of an artificial antigen in a diabetes model and after prolonged administration of vitamin D3. Chronic hyperglycemia occurring in diabetes induced a 2.3-fold decrease of the content of the marker substance 25OHD3, the major precursor of hormonally active forms of vitamin D3, in the serum. The development of vitamin D3 deficiency is accompanied by an impairment of the proliferative activity of T cells and a change in relative numbers of regulatory (CD4+) and cytotoxic (CD8+) lymphocytes. An increase of the content of the phosphorylated p65 subunit of the nuclear factor κB and more intensive translocation of this protein to the nucleus were detected in total lysates of T lymphocytes from the spleen. Moreover, enhancement of the humoral IgG response to intraperitoneal administration of a recombinant B subunit of diphtheria toxin was demonstrated. Impairment of the cellular component of the immune response was accompanied by increased apoptotic death of splenocytes, as is evident from the increased binding of the Annexin V-GFP tag to phosphatidyl serine residues exposed on the external side of the plasmalemma during apoptosis. Prolonged administration of vitamin D3 (during 2 months; dose 20 IU) promoted the normalization of proliferative activity and the relative size of T-cell subpopulations, led to a decrease of the content of the phosphorylated p65 subunit of NF-κB, and improved the balance of the secretion of IgG targeting the artificial antigen in diabetic animals. These changes were accompanied by a decrease in the number of apoptotic events in the entire splenocyte population. The results of the present study demonstrate the important role of vitamin D3 in the regulation of the functions of the immune system in type 1 diabetes.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Harrison, L.C., Honeyman, M.C., Morahan, G., Wentworth, J.M., Elkassaby, S., Colman, P.G., and Fourlanos, S., Type 1 diabetes: lessons for other autoimmune diseases?, J. Autoimmun., 2008, vol. 31, no. 3, pp. 306–310.

    Article  CAS  PubMed  Google Scholar 

  2. Aanstoot, H.J., Anderson, B.J., Daneman, D., Danne, T., Donaghue, K., Kaufman, F., Rea, R.R., and Uchigata, Y., The global burden of youth diabetes: perspectives and potential, Pediatr. Diabet., 2007, suppl. 8, pp. 1–44.

    Google Scholar 

  3. Rubinstein, R., Genaro, A.M., Motta, A., Cremaschi, G., and Wald, M.R., Impaired immune responses in streptozotocin- induced type i diabetes in mice. involvement of high glucose, Clin. Exp. Immunol., 2008, vol. 154, no. 2, pp. 235–246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jailwala, P., Waukau, J., Glisic, S., Jana, S., Ehlenbach, S., Hessner, M., Alemzadeh, R., Matsuyama, S., Laud, P., Wang, X., and Ghosh, S., Apoptosis of CD4+ CD25+ T cells in type 1 diabetes may be partially mediated by IL-2 deprivation, PLoS One, 2009, vol. 4, no. 8, pp. 1–22.

    Article  Google Scholar 

  5. Vignali, D.A., Collison, L.W., and Workman, C.J., How regulatory T cells work, Nat. Rev. Immunol., 2008, vol. 8, no. 7, pp. 523–532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yoon, J.W. and Jun, H.S., Autoimmune destruction of pancreatic beta cells, Am. J. Ther., 2005, vol. 12, no. 6, pp. 580–591.

    Article  PubMed  Google Scholar 

  7. Tsai, S., Shameli, A., and Santamaria, P., CD8+ T cells in type 1 diabetes, Adv. Immunol., 2008, vol. 100, pp. 79–124.

    Article  CAS  PubMed  Google Scholar 

  8. Phillips, J.M., Parish, N.M., Raine, T., Bland, C., Sawyer, Y., De La Pena H., and Cooke, A., Type 1 diabetes development requires both CD4+ and CD8+ T cells and can be reversed by non-depleting antibodies targeting both T cell populations, Rev. Diabet. Stud., 2009, vol. 6, no. 2, pp. 97–103.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Hultcrantz, M., Jacobson, S., Hill, N.J., Santamaria, P., and Flodstrom-Tullberg, M., The target cell response to cytokines governs the autoreactive T cell repertoire in the pancreas of nod mice, Diabetologia, 2009, vol. 52, no. 2, pp. 299–305.

    Article  CAS  PubMed  Google Scholar 

  10. Ilonen, J., Surcel, H.M., and Käär, M.L., Abnormalities within CD4 and CD8 T lymphocytes subsets in type 1 (insulin-dependent) diabetes, Clin. Exp. Immunol., 1991, vol. 85, no. 2, pp. 278–281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pacifici, R., T cells and postmenopausal osteoporosis in murine models, Arthrit. Res. Ther., 2007, vol. 9, no. 2, pp. 102–106.

    Article  Google Scholar 

  12. Aranow, C., Vitamin D and the immune system, J. Investig. Med., 2011, vol. 59, no. 6, pp. 881–886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Holick, M.F., Vitamin D deficiency, N. Engl. J. Med., 2007, vol. 357, pp. 266–281.

    Article  CAS  PubMed  Google Scholar 

  14. Baeke, F., Korf, H., Overbergh, L., Verstuyf, A., Gysemans, C., and Mathieu, C., Human T lymphocytes are direct targets of 1,25-dihydroxyvitamin D3 in the immune system, J. Steroid Biochem. Mol. Biol., 2010, vol. 121, nos. 1–2, pp. 221–227.

    Article  CAS  PubMed  Google Scholar 

  15. Yin, K. and Agrawal, D.K., Vitamin D and inflammatory diseases, J. Inflamm. Res., 2014, vol. 7, no. 29, pp. 69–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kongsbak, M., Levring, T.B., Geisler, C., and von Essen, M.R., The vitamin D receptor and T cell function, Front. Immunol., 2013, vol. 4, pp. 148–158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. VanEtten, E., Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts, J. Steroid. Biochem. Mol. Biol., 2005, vol. 97, nos. 1–2, pp. 93–101.

    CAS  Google Scholar 

  18. Mosman, T., Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assay, J. Immunol. Methods, 1983, vol. 65, no. 1, pp. 55–63.

    Article  Google Scholar 

  19. Stavniichuk, R., Obrosov, A.A., Drel, V.R., Nadler, J.L., Obrosova, I.G., and Yorek, M.A., 12/15-lipoxygenase inhibition counteracts MAPK phosphorylation in mouse and cell culture models of diabetic peripheral neuropathy, J. Diabet. Mellitus, 2013, vol. 3, no. 3.

  20. Harper, D.R. and Murphy, G., Nonuniform variation in band pattern with luminol/horseradish peroxidase Western blotting, Anal. Biochem., 1991, vol. 192, no. 1, pp. 59–63.

    Article  CAS  PubMed  Google Scholar 

  21. Ayroldi, E., Migliorati, G., Bruscoli, S., Marchetti, C., Zollo, O., Cannarile, L., D’Adamio, F., and Riccardi, C., Modulation of T-cell activation by the glucocorticoidinduced leucine zipper factor via inhibition of nuclear factor kappaB, Blood, 2001, vol. 98, no. 3, pp. 743–753.

    Article  CAS  PubMed  Google Scholar 

  22. Sun, C., Sun, L., Ma, H., Peng, J., Zhen, Y., Duan, K., Liu, G., Ding, W., and Zhao, Y., The phenotype and functional alterations of macrophages in mice with hyperglycemia for long term, J. Cell Physiol., 2012, vol. 227, no. 4, pp. 1670–1679.

    Article  CAS  PubMed  Google Scholar 

  23. Wang, J., Lv, C., Xie, T., and Ouyang, J., The variance of peripheral blood lymphocyte subsets of streptozotocin-induced diabetic mice after bone marrow transplantation, Int. J. Clin. Exp. Med., 2015, vol. 8, no. 3, pp. 4115–4121.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Eman, M.S., Nidhal, A.M., and Majed, A.J., Abnormal lymphocyte subsets in children with type 1 diabetes mellitus, Menoufia Medk, 2008, vol. 7, no. 1, pp. 9–14.

    Google Scholar 

  25. Reinert-Hartwall, L., Honkanen, J., Salo, H.M., Nieminen, J.K., Luopajärvi, K., Härkönen, T., Veijola, R., Simell, O., Ilonen, J., Peet, A., Tillmann, V., Knip, M., and Vaarala, O., Th1/Th17 plasticity is a marker of advanced cell autoimmunity and impaired glucose tolerance in humans, J. Immunol., 2015, vol. 194, no. 1, pp. 68–75.

    Article  PubMed  Google Scholar 

  26. Labudzynskyi, D.O., Shymanskyy, I.O., Riasnyi, V.M., and Veliky, M.M., Vitamin D3 bioavailability and functional activity of peripheral blood phagocytes in experimental type 1 diabetes, Ukr. Biochem. J., 2014, vol. 86, no. 2, pp. 107–118.

    Article  CAS  Google Scholar 

  27. Yan, G., Shi, L., Penfornis, A., and Faustman, D.L., Impaired processing and presentation by MHC class II proteins in human diabetic cells, J. Immunol., 2003, vol. 170, no. 1, pp. 620–627.

    Article  CAS  PubMed  Google Scholar 

  28. Sakowicz-Burkiewicz, M., Kocbuch, K., Grden, M., Szutowicz, A., and Pawelczyk, T., Diabetes-induced decrease of adenosine kinase expression impairs the proliferation potential of diabetic rat T lymphocytes, Immunology, 2006, vol. 118, no. 3, pp. 402–412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Green, D.R. and Ware, C.F., Fas-ligand: privilege and peril, Proc. Natl. Acad. Sci. U. S. A., 1997, vol. 94, no. 12, pp. 5986–5990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kang, O.H., Jang, H.J., Chae, H.S., Oh, Y.C., Choi, J.G., Lee, Y.S., Kim, Y.C., Park, H., and Kwon, D.Y., Antiinflammatory mechanisms of resveratrol in activated hmc-1 cells: pivotal roles of NF-kappaB and MAPK, Pharmacol. Res., 2009, vol. 59, no. 5, pp. 330–337.

    Article  CAS  PubMed  Google Scholar 

  31. Gharagozloo, M., Velardi, E., Bruscoli, S., Agostini, M., Di Sante, M., Donato, V., Amirghofran, Z., and Riccardi, C., Silymarin suppress CD4+ T cell activation and proliferation: effects on NF-kB activity and IL-2 production, Pharmacol. Res., 2010, vol. 61, no. 5, pp. 405–409.

    Article  CAS  PubMed  Google Scholar 

  32. Wong, F.S. and Wen, L., B cells in autoimmune diabetes, Rev. Diabet. Stud., 2005, vol. 2, no. 3, pp. 121–135.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Tarui, T., Majumdar, M., Miles, L.A., Ruf, W., and Takada, Y., Plasmin-induced migration of endothelial cells a potential target for the anti-angiogenic action of angiostatin, J. Biol. Chem., 2002, vol. 277, no. 37, pp. 33564–33570.

    Article  CAS  PubMed  Google Scholar 

  34. Mahmoud, M.H., Badr, G., Badr, B.M., Kassem, A.U., and Mohamed, M.S., Elevated IFNalpha/beta levels in a streptozotocin-induced type I diabetic mouse model promote oxidative stress and mediate depletion of spleen-homing CD8+ T cells by apoptosis through impaired CCL21/CCR7 axis and IL-7/CD127 signaling, Cell Signal., 2015, vol. 27, no. 10, pp. 2110–2119.

    Article  CAS  PubMed  Google Scholar 

  35. Saggese, G., Vierucci, F., Boot, A.M., Czech-Kowalska, J., Weber, G., Mallet, E., Fanos, M., Shaw, N.J., and Holick, M.F., Vitamin D in childhood and adolescence: an expert position statement, Eur. J. Pediatr., 2015, vol. 174, no. 5, pp. 565–576.

    Article  CAS  PubMed  Google Scholar 

  36. Yunzi, C., Jing, Z., Xin, G., Jie, D., Dilip, K.D., and Yan, C.L., Vitamin D receptor inhibits nuclear factor B activation by interacting with IB kinase protein, J. Biol. Chem., 2013, vol. 288, no. 27, pp. 19450–19458.

    Article  Google Scholar 

  37. Chen, S., Sims, G.P., Chen, X.X., Gu, Y.Y., Chen, S., and Lipsky, P.E., Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation, J. Immunol, 2007, vol. 179, pp. 1634–1647.

    Article  CAS  PubMed  Google Scholar 

  38. Bao, B.Y., Ting, H.J., Hsu, J.W., and Lee, Y.F., Protective role of 1 alpha, 25-dihydroxyvitamin D3 against oxidative stress in nonmalignant human prostate epithelial cells, Int. J. Cancer, 2008, vol. 122, no. 12, pp. 2699–2706.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine

    D. O. Labudzynskyi, K. U. Manoylov, I. O. Shymanskyy & M. M. Veliky

Authors
  1. D. O. Labudzynskyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. U. Manoylov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. O. Shymanskyy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. M. Veliky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D. O. Labudzynskyi.

Additional information

Original Ukrainian Text © D.O. Labudzynskyi, K.U. Manoylov, I.O. Shymanskyy, M.M. Veliky, 2016, published in Tsitologiya i Genetika, 2016, Vol. 50, No. 4, pp. 38–49.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Labudzynskyi, D.O., Manoylov, K.U., Shymanskyy, I.O. et al. Immunoregulatory effects of vitamin D3 in experimentally induced type 1 diabetes. Cytol. Genet. 50, 231–240 (2016). https://doi.org/10.3103/S0095452716040071

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.3103/S0095452716040071

Keywords

Search

Navigation