Skip to main content

Advertisement

SpringerLink
Log in

Contribution of GPR30 for 1,25 dihydroxyvitamin D3 protection in EAE

  • Original Paper
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Previous studies have demonstrated that vitamin D3-mediated protection in EAE occurs only in females and is dependent on the presence of diestrus levels of 17β-estradiol (E2). To evaluate the role of estrogen receptors in vitamin D3 treatment of EAE, we compared disease severity, CNS histopathology and immunological responses in vehicle and calcitrol (1,25 dihydroxyvitamin D3) treated WT C57BL/6 mice vs. GPR30 membrane estrogen receptor (MER) knockout mice with MOG-35-55 peptide-induced EAE. Our results demonstrated that vitamin D3-mediated prevention of clinical signs, CNS cellular lesions and demyelination observed in WT mice was abrogated in GPR30-KO mice with EAE. Regulatory effects of vitamin D3 treatment that were MER dependent included increased levels of IL-10 and IL-6 secreted by MOG peptide-reactive splenocytes and increased expression of CCL5, CCR1 & CCR3 in spleen tissue. These results demonstrate for the first time that the MER is a key contributor to the E2-dependent effects of vitamin D3-mediated protection in EAE.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Byrne IM, Flanagan L, Tenniswood MP, Welsh J (2000) Identification of a hormone-responsive promoter immediately upstream of exon 1c in the human vitamin D receptor gene. Endocrinology 141:2829–2836

    Article  PubMed  CAS  Google Scholar 

  • Carlyle IP (1997) Multiple sclerosis: a geographical hypothesis. Med Hypotheses 49(6):477–486

    Article  PubMed  CAS  Google Scholar 

  • Filardo EJ, Quinn JA, Bland KI, Frackelton AR Jr (2000) Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol 14(10):1649–1660

    Article  PubMed  CAS  Google Scholar 

  • Goverman JM (2011) Immune tolerance in multiple sclerosis. Immunol Rev 241(1):228–240

    Article  PubMed  CAS  Google Scholar 

  • Harari M, Dramsdahl E, Shany S, Baumfeld Y, Ingber A, Novack V, Sukenik S (2011) Increased vitamin D serum levels correlate with clinical improvement of rheumatic diseases after Dead Sea climatotherapy. Isr Med Assoc J 13(4):212–215

    PubMed  Google Scholar 

  • Lonergan R, Kinsella K, Fitzpatrick P, Brady J, Murray B, Dunne C, Hagan R, Duggan M, Jordan S, McKenna M, Hutchinson M, Tubridy N (2011) Multiple sclerosis prevalence in Ireland: relationship to vitamin D status and HLA genotype. J Neurol Neurosurg Psychiatry 82(3):317–322

    Article  PubMed  CAS  Google Scholar 

  • Mayne CG, Spanier JA, Relland LM, Williams CB, Hayes CE (2011) 1,25-dihydrocyvitamin D3 acts direclty on the T lymphocyte vitamin D receptor to inhibit experimental autoimmune encephalomyelits. European Journal of Immunology 41:822–832

    Article  PubMed  CAS  Google Scholar 

  • Mosayebi G, Ghazavi A, Ghasami K, Jand Y, Kokhaei P (2011) Therapeutic effect of vitamin D3 in multiple sclerosis patients. Immunol Invest 40(6):627–639

    Article  PubMed  CAS  Google Scholar 

  • Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A (2006) Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296(23):2832–2838

    Article  PubMed  CAS  Google Scholar 

  • Nashold FE, Spach KM, Spanier JA, Hayes CE (2009) Estrogen controls vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin D3 metabolism and receptor expression. J Immunol 183(6):3672–3681

    Article  PubMed  CAS  Google Scholar 

  • Ramagopalan SV, Handel AE, Giovannoni G, Rutherford Siegel S, Ebers GC, Chaplin G (2011) Relationship of UV exposure to prevalence of multiple sclerosis in England. Neurology 76(16):1410–1414

    Article  PubMed  CAS  Google Scholar 

  • Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307(5715):1625–1630

    Article  PubMed  CAS  Google Scholar 

  • Sadovnick AD (2009) European Charcot Foundation Lecture: the natural history of multiple sclerosis and gender. J Neurol Sci 286(1–2):1–5

    Article  PubMed  CAS  Google Scholar 

  • Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, Fonseca SG, Van Grevenynghe J, Boulassel MR, Bruneau J, Shoukry NH, Routy J-P, Douek DC, Haddad EK, Sekaly R-P (2010) Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med 16(4):452–459

    Article  PubMed  CAS  Google Scholar 

  • Smolders J (2011) Vitamin D and multiple sclerosis: correlation, causality, and controversy. Autoimmune Dis doi:10.4061/2011/629538

  • Spach KM, Hayes CE (2005) Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice. J Immunol 175(6):4119–4126

    PubMed  CAS  Google Scholar 

  • Takeda M, Yamashita T, Sasaki N, Nakajima K, Kita T, Shinohara M, Ishida T, Hirata K (2010) Oral administration of an active form of vitamin D3 (calcitriol) decreases atherosclerosis in mice by inducing regulatory T cells and immature dendritic cells with tolerogenic functions. Arterioscler Thromb Vasc Biol 30(12):2495–2503

    Article  PubMed  CAS  Google Scholar 

  • Vieira VM, Hart JE, Webster TF, Weinberg J, Puett R, Laden F, Costenbader KH, Karlson EW (2010) Association between residences in U.S. northern latitudes and rheumatoid arthritis: A spatial analysis of the Nurses’ Health Study. Environ Health Perspect 118(7):957–961

    Article  PubMed  Google Scholar 

  • Vukusic S, Hutchinson M, Hours M, Moreau T, Cortinovis-Tourniaire P, Adeleine P, Confavreux C, The Pregnancy In Multiple Sclerosis Group (2004) Pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of post-partum relapse. Brain 127(Pt 6):1353–1360

    Article  PubMed  Google Scholar 

  • Wang C, Dehghani B, Li Y, Kaler L, Proctor T, Vandenbark AA, Offner H (2009) Membrane estrogen receptor agonist regulates EAE through upregulation of programmed death-1. Journal of Immunology 182:3294–3303

    Article  CAS  Google Scholar 

  • Wang C, Dehghani B, Magrisso IJ, Rick EA, Bonhomme E, Cody DB, Elenich LA, Subramanian S, Murphy SJ, Kelly MJ, Rosenbaum JS, Vandenbark AA, Offner H (2008) GPR30 contributes to estrogen-induced thymic atrophy. Mol Endocrinol 22(3):636–648

    Article  PubMed  CAS  Google Scholar 

  • Wu GF, Alvarez E (2011) The immunopathophysiology of multiple sclerosis. Neurol Clin 29(2):257–278

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Ms. Eva Niehaus for assistance in preparing the manuscript. This work was supported by National Multiple Sclerosis Society grant RG3107-D-6. This material is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.

Conflict of interest statement

The authors have no financial conflicts of interest.

Author information

Authors and Affiliations

  1. Neuroimmunology Research, R&D-31, Portland Veterans Affairs Medical Center, 3710 SW US Veterans Hospital Rd, Portland, OR, 97239, USA

    Sandhya Subramanian, Lisa M. Miller, Arthur A. Vandenbark & Halina Offner

  2. Department of Neurology, Oregon Health & Science University, Portland, OR, 97239, USA

    Lisa M. Miller, Arthur A. Vandenbark & Halina Offner

  3. Department of Pathology, Oregon Health & Science University, Portland, OR, 97239, USA

    Marjorie R. Grafe

  4. Sr. Research Career Scientist, Research Service, Department of Veterans Affairs Medical Center, Portland, OR, 97239, USA

    Arthur A. Vandenbark

  5. Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, 97239, USA

    Arthur A. Vandenbark

  6. Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR, 97239, USA

    Halina Offner

Authors
  1. Sandhya Subramanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lisa M. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marjorie R. Grafe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arthur A. Vandenbark
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Halina Offner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Halina Offner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Subramanian, S., Miller, L.M., Grafe, M.R. et al. Contribution of GPR30 for 1,25 dihydroxyvitamin D3 protection in EAE. Metab Brain Dis 27, 29–35 (2012). https://doi.org/10.1007/s11011-011-9266-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-011-9266-6

Keywords

Search

Navigation