FTY720 mediates cytochrome c release from mitochondria during rat thymocyte apoptosis.
FTY720 is known to not only accelerate lymphocyte homing to secondary lymphoid organs but also induce apoptosis in lymphocytes. To investigate the effect of FTY720 in rat thymocytes, rats were intramuscularly injected with 10 mg/kg/day of FTY720. Light microscopy revealed obvious reductions in the size of the cortical region of thymuses treated with FTY720. FTY720 significantly reduced the total number of thymocytes, particularly affecting the CD4(+)8(+)TCRalphabeta(negative/low) population. TUNEL analysis showed that thymocyte apoptosis was induced in the cortical region and western blotting revealed activated caspase-3 and -6. Furthermore, caspase-9 was activated and the level of cytochrome c was increased. In contrast, the protein level of Bax did not increase following FTY720 treatment, suggesting that FTY720 may have perturbed mitochondrial function. Therefore, FTY720-induced apoptosis is initiated by the release of cytochrome c from mitochondria, resulting in the activation of caspases in rat thymocytes.
Matsumura
Masafumi
M
Department of Urology, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan. m-matsu@ta2.so-net.ne.jp
Tsuchida
Masahiro
M
Isoyama
Naohito
N
Takai
Kimio
K
Matsuyama
Hideyasu
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015704:CD4 Antigens / Q000096:biosynthesis; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D045304:Cytochromes c / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D007273:Injections, Intramuscular; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011409:Propylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects; D051381:Rats; D011919:Rats, Inbred Strains; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis; D013110:Sphingosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000187:drug effects* / Q000473:pathology
D015704:CD4 Antigens; D011409:Propylene Glycols; D011948:Receptors, Antigen, T-Cell; D045304:Cytochromes c; D020169:Caspases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine