Molecular Neurobiology

, Volume 50, Issue 3, pp 733–743

Vitamin D Therapy in Experimental Allergic Encephalomyelitis Could be Limited by Opposing Effects of Sphingosine 1-Phosphate and Gelsolin Dysregulation

  • Yanyan Zhu
  • Zhaoyu Qin
  • Jifang Gao
  • Mingchong Yang
  • Yanjiang Qin
  • Ting Shen
  • Shilian Liu
Article

DOI: 10.1007/s12035-014-8686-9

Cite this article as:
Zhu, Y., Qin, Z., Gao, J. et al. Mol Neurobiol (2014) 50: 733. doi:10.1007/s12035-014-8686-9
  • 295 Downloads

Abstract

Several studies support a protective effect of vitamin D on multiple sclerosis and experimental allergic encephalomyelitis (EAE), but the mechanisms of these favorable effects are unclear. Our study demonstrates that sphingosine 1-phosphate (S1P) is upregulated in the serum and spinal cords of EAE rats, but that vitamin D reverses the upregulation to alleviate inflammation. Vitamin D, however, cannot prevent the disease process, suggesting that other factors may be involved. To identify additional factors that might limit vitamin D efficacy, we assessed the effects of vitamin D on plasma gelsolin (pGSN), a regulator of S1P that is downregulated in the CSF of MS patients. Our results show that pGSN is downregulated in the serum of EAE rats, whereas its cellular form, cytoplasmic gelsolin (cGSN), is upregulated in the spinal cord of EAE rats. Importantly, vitamin D causes a downregulation of both pGSN and cGSN, which may counteract the positive effects of S1P decrease. Furthermore, 48 and 42 kDa caspase-3 cleavage products of cGSN are detected in EAE spinal cords, suggesting enhanced apoptotic activity, but these cleaved products undergo a similar decrease upon vitamin D treatment. To directly test the role of cGSN in the apoptotic process, we performed RNA interference in PC-12, a rat sympathetic nerve cell line. Results verify that cGSN suppresses apoptosis induced by TNF-α. Collectively, these results support a therapeutic effect of vitamin D that is derived from its ability to reduce S1P, but is limited by its simultaneous effect in reducing pGSN and cGSN. Based on these observations, we postulate that combined therapy with recombinant human pGSN and vitamin D may produce more beneficial effect in treating multiple sclerosis.

Keywords

Multiple sclerosisVitamin DPlasma gelsolinSphingosine 1-phosphateCytoplasmic gelsolin

Abbreviations

Caspase-3

Cysteinyl aspartate-specific protease-3

cGSN

Cytoplasmic gelsolin

CSF

Cerebrospinal fluid

EAE

Experimental allergic encephalomyelitis

GSN

Gelsolin

MS

Multiple sclerosis

OND

Neurological disorder other than MS

pGSN

Plasma gelsolin

S1P

Sphingosine 1-phosphate

Supplementary material

12035_2014_8686_Fig7_ESM.gif (26 kb)
Supplementary Fig. 1

Establishment of the EAE rat model. A, The weight of EAE rats decreases between days 9 and 14 after MBP injection and gradually increases after day15. However, the weight of control rats gradually and consistently increases. B, Disease symptoms were monitored over 25 days of EAE induction. The symptom emerged at approximately day10, peaked on the day 13, and disappeared at day19. C, Pathological section of inflammatory lesions stained with hematoxylin and eosin. No obvious inflammation was observed in the cerebrum of control (C-I) or acute stage EAE (C-II) rats; or in the spinal cord of control (C-III) or pre-stage (C-IV) rats. However, the spinal cord of EAE rats in the acute stage (C-V) developed serious lesions. (×400 magnification, scale bar 10 μm) (GIF 26 kb)

12035_2014_8686_MOESM1_ESM.tif (1 mb)
High resolution image (TIFF 1,030 kb)
12035_2014_8686_MOESM2_ESM.docx (233 kb)
ESM 2(DOCX 233 kb)
12035_2014_8686_MOESM3_ESM.docx (499 kb)
ESM 3(DOCX 498 kb)
12035_2014_8686_MOESM4_ESM.docx (14 kb)
ESM 4(DOCX 14 kb)
12035_2014_8686_MOESM5_ESM.docx (18 kb)
ESM 5(DOCX 18 kb)
12035_2014_8686_MOESM6_ESM.docx (13 kb)
ESM 6(DOCX 12 kb)
12035_2014_8686_MOESM7_ESM.docx (13 kb)
ESM 7(DOCX 12 kb)

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Yanyan Zhu
    • 1
  • Zhaoyu Qin
    • 2
  • Jifang Gao
    • 1
  • Mingchong Yang
    • 3
  • Yanjiang Qin
    • 4
  • Ting Shen
    • 5
  • Shilian Liu
    • 1
  1. 1.Department of Biochemistry and Molecular Biology, School of MedicineShandong UniversityJinanPeople’s Republic of China
  2. 2.Laboratory of Systems Biology, Institutes of Biomedical SciencesFudan UniversityShanghaiChina
  3. 3.Institutes of Biochemistry and Molecular Biology, School of Life ScienceShandong UniversityJinanChina
  4. 4.Department of NeurologyQilu Hospital of Shandong UniversityJinanChina
  5. 5.School of Medicine and Life ScienceUniversity of JinanJinanChina