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| Status |
Public on Apr 16, 2011 |
| Title |
Non-phosphorylated FTY720 induces apoptosis of human microglia by activating SREBP2 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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-inflammmatory 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 microM, 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, a S1P1 selective agonist 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.
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| Overall design |
The HMO6 cell line was established by immortalizing cultured microglia isolated from human embryonic telencephalon tissues with a retroviral vector PASK1.2 encoding v-myc oncogene (Nagai et al. Neurobiol. Dis. 8: 1057-1068, 2001). HMO6 cells express the markers of the microglia/macrophage lineage cells, including CD11b, CD68, CD86, HLA-ABC, HLA-DR, and ricinus communis agglutinin lectin-1 (RCA), serving as a model of human microglia both in vitro and in vivo. The cells were exposed for 2 hours to 10 microM FTY720-non-P dissolved in dimethyl sulfoxide (DMSO) or ethanol or exposed to the vehicle.
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| Contributor(s) |
Satoh J, Tabunoki H |
| Citation(s) |
21519925 |
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| Submission date |
Apr 15, 2011 |
| Last update date |
Jul 26, 2018 |
| Contact name |
Jun-ichi Satoh |
| E-mail(s) |
satoj@my-pharm.ac.jp
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| Organization name |
Meiji Pharmaceutical University
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| Department |
Bioinformatics
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| Lab |
Molecular Neuropathology
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| Street address |
2-522-1 Noshio, Kiyose
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| City |
Tokyo |
| ZIP/Postal code |
204-8588 |
| Country |
Japan |
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| Platforms (1) |
| GPL6244 |
[HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array [transcript (gene) version] |
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| Samples (4)
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| GSM709682 |
Non-phosphorylated FTY720 induces apoptosis of human microglia by activating SREBP2(#1) |
| GSM709683 |
Non-phosphorylated FTY720 induces apoptosis of human microglia by activating SREBP2(#2) |
| GSM709684 |
Non-phosphorylated FTY720 induces apoptosis of human microglia by activating SREBP2(#3) |
| GSM709685 |
Non-phosphorylated FTY720 induces apoptosis of human microglia by activating SREBP2(#4) |
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| Relations |
| BioProject |
PRJNA138895 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE28642_RAW.tar |
17.3 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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