Activation of caspases and mitochondria in FTY720-mediated apoptosis in human T cell line Jurkat.
FTY720, a novel immunosuppressive drug originally derived from a metabolite from Isaria sinclairii, is known to induce apoptosis in lymphocytes. In this study, we investigated the involvement of caspases and mitochondria in FTY720-mediated apoptosis using Jurkat cells, a human T cell line. Our results indicated that FTY720-induced activation of caspases 2, 3, 6, 8, 9 and 10, whereas caspases 1 and 5 were not activated. We also observed in the FTY720-treated cells a loss of mitochondrial membrane potential, a release of cytochrome c into cytosol and an exposed phosphatidylserine (PS) at the outer surface of the cell membrane. Pretreatment with a peptide inhibitor, benzyloxycarbonyl-Asp-CH2COC-2, 6-dichlorobenzene (Z-Asp-CH2-DCB), prevented apoptosis and externalization of phosphatidylserine, whereas the inhibitor did not prevent the mitochondrial events. This suggests that caspases may play a role downstream of the mitochondrial pathway. Therefore, caspase cascade in FTY720-treated cells may be initiated by activation of mitochondria.
Fujino
M
M
Department of Experimental Surgery and Bioengineering, National Children's Medical Research Center, Tokyo, Japan.
Li
X K
XK
Guo
L
L
Amano
T
T
Suzuki
S
S
D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007202:Indicators and Reagents; D019169:Jurkat Cells; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D011409:Propylene Glycols / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives
D061945:Caspase Inhibitors; D002843:Chromatin; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; D011409:Propylene Glycols; D011506:Proteins; D020169:Caspases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine