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Fingolimod ameliorates the development of experimental autoimmune encephalomyelitis by inhibiting Akt-mTOR axis in mice.
Int Immunopharmacol 2016; 30:171-178II

Abstract

Fingolimod is a new immunosuppressive agent approved by Food and Drug Administration (FDA) for treating multiple sclerosis (MS). It acts as a functional antagonist to downregulate the S1P1 receptor, which is known to signal through the Akt-mTOR pathway. We investigated the mechanism of fingolimod action in the classical animal model of MS: experimental autoimmune encephalomyelitis (EAE). Fingolimod treatment significantly reduced clinical scores and histopathology in this model, even when treatment was begun after the onset of pathology. The Akt-mTOR signaling pathway was shown to be activated in the EAE model, by measuring the abundance of downstream activation markers, pAkt and ps6k. And this pathway was inhibited when EAE mice were treated with fingolimod. Mice with EAE exhibited an increased frequency of Th1 cells in the spleen, with concomitant increases in the mRNA levels of Tbet and Ifng and increased IFN-γ production by activated splenocytes; the frequency of Treg cells, as well as mRNA levels of Foxp3 and Tgfb, was reduced, as was TGF-β production by activated splenocytes. After treatment with fingolimod, these parameters were reversed, suggesting that fingolimod treatment inhibits the Akt-mTOR axis in EAE, which affects the differentiation and function of Th1 and Treg cells. These results provide an insight into the mechanism of action of fingolimod treatment and may provide new ideas for treating EAE and MS.

Authors+Show Affiliations

Department of Neurology, Key Laboratory of Hebei Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.Department of Neurology, Key Laboratory of Hebei Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.Department of Neurosurgery, North China Petroleum Bureau General Hospital of Hebei Medical University, Renqiu, 062552, Hebei, China.Department of Neurology, Key Laboratory of Hebei Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.Department of Neurology, Key Laboratory of Hebei Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.Department of Neurology, Key Laboratory of Hebei Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.Department of Neurology, Key Laboratory of Hebei Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China. Electronic address: guoli6105@163.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26632437

Citation

Hou, Huiqing, et al. "Fingolimod Ameliorates the Development of Experimental Autoimmune Encephalomyelitis By Inhibiting Akt-mTOR Axis in Mice." International Immunopharmacology, vol. 30, 2016, pp. 171-178.
Hou H, Cao R, Miao J, et al. Fingolimod ameliorates the development of experimental autoimmune encephalomyelitis by inhibiting Akt-mTOR axis in mice. Int Immunopharmacol. 2016;30:171-178.
Hou, H., Cao, R., Miao, J., Sun, Y., Liu, X., Song, X., & Guo, L. (2016). Fingolimod ameliorates the development of experimental autoimmune encephalomyelitis by inhibiting Akt-mTOR axis in mice. International Immunopharmacology, 30, pp. 171-178. doi:10.1016/j.intimp.2015.11.024.
Hou H, et al. Fingolimod Ameliorates the Development of Experimental Autoimmune Encephalomyelitis By Inhibiting Akt-mTOR Axis in Mice. Int Immunopharmacol. 2016;30:171-178. PubMed PMID: 26632437.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fingolimod ameliorates the development of experimental autoimmune encephalomyelitis by inhibiting Akt-mTOR axis in mice. AU - Hou,Huiqing, AU - Cao,Runjing, AU - Miao,Jun, AU - Sun,Yafei, AU - Liu,Xiaoqian, AU - Song,Xiujuan, AU - Guo,Li, Y1 - 2015/11/26/ PY - 2015/09/07/received PY - 2015/11/19/revised PY - 2015/11/19/accepted PY - 2015/12/4/entrez PY - 2015/12/4/pubmed PY - 2016/10/1/medline KW - Experimental autoimmune encephalomyelitis KW - Fingolimod KW - Multiple sclerosis KW - Th1 cell KW - Treg cell KW - mTOR SP - 171 EP - 178 JF - International immunopharmacology JO - Int. Immunopharmacol. VL - 30 N2 - Fingolimod is a new immunosuppressive agent approved by Food and Drug Administration (FDA) for treating multiple sclerosis (MS). It acts as a functional antagonist to downregulate the S1P1 receptor, which is known to signal through the Akt-mTOR pathway. We investigated the mechanism of fingolimod action in the classical animal model of MS: experimental autoimmune encephalomyelitis (EAE). Fingolimod treatment significantly reduced clinical scores and histopathology in this model, even when treatment was begun after the onset of pathology. The Akt-mTOR signaling pathway was shown to be activated in the EAE model, by measuring the abundance of downstream activation markers, pAkt and ps6k. And this pathway was inhibited when EAE mice were treated with fingolimod. Mice with EAE exhibited an increased frequency of Th1 cells in the spleen, with concomitant increases in the mRNA levels of Tbet and Ifng and increased IFN-γ production by activated splenocytes; the frequency of Treg cells, as well as mRNA levels of Foxp3 and Tgfb, was reduced, as was TGF-β production by activated splenocytes. After treatment with fingolimod, these parameters were reversed, suggesting that fingolimod treatment inhibits the Akt-mTOR axis in EAE, which affects the differentiation and function of Th1 and Treg cells. These results provide an insight into the mechanism of action of fingolimod treatment and may provide new ideas for treating EAE and MS. SN - 1878-1705 UR - https://www.unboundmedicine.com/medline/citation/26632437/Fingolimod_ameliorates_the_development_of_experimental_autoimmune_encephalomyelitis_by_inhibiting_Akt_mTOR_axis_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1567-5769(15)30192-2 DB - PRIME DP - Unbound Medicine ER -