Different mechanisms for membrane and nuclear damages in apoptosis induced by an immunosuppressant, FTY720.
A novel immunosuppressant, FTY720, that was purified from cultures of Isaria sinclairii has been shown to cause apoptosis of lymphocytes, but its biochemical and molecular mechanisms are largely unknown. In this study, we investigated the signal transduction of FTY720-induced apoptosis in comparison with the Fas-induced apoptosis. Although FTY720 induced nuclear and membrane damages in a dose-dependent manner, nuclear damage, but not membrane damage, was suppressed by the caspase-3 inhibitor, DEVD-FMK. It blocked both the nuclear and membrane damages that were induced by the anti-Fas antibody. Experiments using enucleated cytoplasts also demonstrated that membrane damage was induced by FTY720. However, the ones that were induced by the anti-Fas antibody were not blocked by DEVD-FMK. Exogenously-added sphingolipids partially suppressed the FTY720-induced membrane damage. These results suggest that FTY720 induces membrane damage through the caspase-3-independent pathway that is modulated by sphingolipids.
Nakajima
Hiroo
H
Department of Endocrine, Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-0841, Japan.
Lee
Yun-Sik
YS
Matsuda
Tetsuro
T
Mizuta
Naruhiko
N
Magae
Junji
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019169:Jurkat Cells; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D011409:Propylene Glycols / Q000494:pharmacology*; D013107:Sphingolipids / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D013107:Sphingolipids; D019014:fas Receptor; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine