T cell selective apoptosis by a novel immunosuppressant, FTY720, is closely regulated with Bcl-2.
1. A novel immunosuppressant FTY720 caused a significant decrease in peripheral T lymphocytes, but not in B lymphocytes upon oral administration. This decrease was mainly a result of FTY720-induced apoptosis. In this study, we confirmed FTY720-induced T cell selective apoptosis using lymphoma cell lines in vitro. 2. Viability loss, DNA fragmentation, Annexin V binding, and caspases activation (caspase-3, -8, and -9) were observed in Jurkat cells (T lymphoma cells), but not significantly in BALL-1 cells (B lymphoma cells). These results indicated that FTY720 selectively induced apoptosis in T cell lymphoma to a greater extent than in B cell lymphoma, a finding that is similar to the result observed when FTY720 was treated with T lymphocytes and B lymphocytes in vitro. 3. FTY720 released cytochrome c from mitochondria in Jurkat intact cells as well as from isolated Jurkat mitochondria directly, but not from mitochondria in BALL-1 cells nor from isolated BALL-1 mitochondria. 4. BALL-1 cells and B cells had more abundant mitochondria-localized anti-apoptotic protein Bcl-2 than did Jurkat cells and T cells. 5. FTY720-induced apoptosis is inhibited by the overexpression of Bcl-2, suggesting that the cellular Bcl-2 level regulates the sensitivity to FTY720.
Nagahara
Yukitoshi
Y
Division of Radio Isotopes and Biosafety Research, National Research Institute for Child Health and Development, 3-35-31 Taishido, Setagaya-ku, Tokyo 154-8567, Japan.
Ikekita
Masahiko
M
Shinomiya
Takahisa
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003574:Cytochrome c Group / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019169:Jurkat Cells / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D051381:Rats; D013110:Sphingosine / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003574:Cytochrome c Group; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D019253:Proto-Oncogene Proteins c-bcl-2; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine