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Non-phosphorylated FTY720 induces apoptosis of human microglia by activating SREBP2.
Cell Mol Neurobiol. 2011 Oct; 31(7):1009-20.CM

Abstract

A synthetic analog of sphingosine named FTY720 (Fingolimod), phosphorylated by sphingosine kinase-2, interacts with sphingosine-1-phosphate (S1P) receptors expressed on various cells. FTY720 suppresses the disease activity of multiple sclerosis (MS) chiefly by inhibiting S1P-dependent egress of autoreactive T lymphocytes from secondary lymphoid organs, and possibly by exerting anti-inflammatory and neuroprotective effects directly on brain cells. However, at present, biological effects of FTY720 on human microglia are largely unknown. We studied FTY720-mediated apoptosis of a human microglia cell line HMO6. The exposure of HMO6 cells to non-phosphorylated FTY720 (FTY720-non-P) induced apoptosis in a dose-dependent manner with IC50 of 10.6 ± 2.0 μM, accompanied by the cleavage of caspase-7 and caspase-3 but not of caspase-9. The apoptosis was inhibited by Z-DQMD-FMK, a caspase-3 inhibitor, but not by Pertussis toxin, a Gi protein inhibitor, suramin, a S1P3/S1P5 inhibitor, or W123, a S1P1 competitive antagonist, although HMO6 expressed S1P1, S1P2, and S1P3. Furthermore, both phosphorylated FTY720 (FTY720-P) and SEW2871, S1P1 selective agonists, did not induce apoptosis of HMO6. Genome-wide gene expression profiling and molecular network analysis indicated activation of transcriptional regulation by sterol regulatory element-binding protein (SREBP) in FTY720-non-P-treated HMO6 cells. Western blot verified activation of SREBP2 in these cells, and apoptosis was enhanced by pretreatment with simvastatin, an activator of SREBP2, and by overexpression of the N-terminal fragment of SREBP2. These observations suggest that FTY720-non-P-induced apoptosis of HMO6 human microglia is independent of S1P receptor binding, and positively regulated by the SREBP2-dependent proapoptotic signaling pathway.

Authors+Show Affiliations

Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

21519925

Citation

Yoshino, Takashi, et al. "Non-phosphorylated FTY720 Induces Apoptosis of Human Microglia By Activating SREBP2." Cellular and Molecular Neurobiology, vol. 31, no. 7, 2011, pp. 1009-20.
Yoshino T, Tabunoki H, Sugiyama S, et al. Non-phosphorylated FTY720 induces apoptosis of human microglia by activating SREBP2. Cell Mol Neurobiol. 2011;31(7):1009-20.
Yoshino, T., Tabunoki, H., Sugiyama, S., Ishii, K., Kim, S. U., & Satoh, J. (2011). Non-phosphorylated FTY720 induces apoptosis of human microglia by activating SREBP2. Cellular and Molecular Neurobiology, 31(7), 1009-20. https://doi.org/10.1007/s10571-011-9698-x
Yoshino T, et al. Non-phosphorylated FTY720 Induces Apoptosis of Human Microglia By Activating SREBP2. Cell Mol Neurobiol. 2011;31(7):1009-20. PubMed PMID: 21519925.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Non-phosphorylated FTY720 induces apoptosis of human microglia by activating SREBP2. AU - Yoshino,Takashi, AU - Tabunoki,Hiroko, AU - Sugiyama,Shigeo, AU - Ishii,Keitaro, AU - Kim,Seung U, AU - Satoh,Jun-Ichi, Y1 - 2011/04/26/ PY - 2011/02/03/received PY - 2011/04/14/accepted PY - 2011/4/27/entrez PY - 2011/4/27/pubmed PY - 2012/4/17/medline SP - 1009 EP - 20 JF - Cellular and molecular neurobiology JO - Cell. Mol. Neurobiol. VL - 31 IS - 7 N2 - A synthetic analog of sphingosine named FTY720 (Fingolimod), phosphorylated by sphingosine kinase-2, interacts with sphingosine-1-phosphate (S1P) receptors expressed on various cells. FTY720 suppresses the disease activity of multiple sclerosis (MS) chiefly by inhibiting S1P-dependent egress of autoreactive T lymphocytes from secondary lymphoid organs, and possibly by exerting anti-inflammatory and neuroprotective effects directly on brain cells. However, at present, biological effects of FTY720 on human microglia are largely unknown. We studied FTY720-mediated apoptosis of a human microglia cell line HMO6. The exposure of HMO6 cells to non-phosphorylated FTY720 (FTY720-non-P) induced apoptosis in a dose-dependent manner with IC50 of 10.6 ± 2.0 μM, accompanied by the cleavage of caspase-7 and caspase-3 but not of caspase-9. The apoptosis was inhibited by Z-DQMD-FMK, a caspase-3 inhibitor, but not by Pertussis toxin, a Gi protein inhibitor, suramin, a S1P3/S1P5 inhibitor, or W123, a S1P1 competitive antagonist, although HMO6 expressed S1P1, S1P2, and S1P3. Furthermore, both phosphorylated FTY720 (FTY720-P) and SEW2871, S1P1 selective agonists, did not induce apoptosis of HMO6. Genome-wide gene expression profiling and molecular network analysis indicated activation of transcriptional regulation by sterol regulatory element-binding protein (SREBP) in FTY720-non-P-treated HMO6 cells. Western blot verified activation of SREBP2 in these cells, and apoptosis was enhanced by pretreatment with simvastatin, an activator of SREBP2, and by overexpression of the N-terminal fragment of SREBP2. These observations suggest that FTY720-non-P-induced apoptosis of HMO6 human microglia is independent of S1P receptor binding, and positively regulated by the SREBP2-dependent proapoptotic signaling pathway. SN - 1573-6830 UR - https://www.unboundmedicine.com/medline/citation/21519925/Non_phosphorylated_FTY720_induces_apoptosis_of_human_microglia_by_activating_SREBP2_ L2 - https://doi.org/10.1007/s10571-011-9698-x DB - PRIME DP - Unbound Medicine ER -