Ochratoxin A induces apoptosis in human lymphocytes through down regulation of Bcl-xL.
Ochratoxin A (OTA) is a widespread mycotoxin contaminating feed and food. Besides its potent nephrotoxicity, OTA also affects the immune system. We demonstrate here a role for Bcl-x(L) in OTA-induced apoptosis in human lymphocytes. In particular, human peripheral blood lymphocytes and the human lymphoid T cell line, Kit 225 cells, underwent apoptosis in a time- and dose-dependent manner. This apoptosis was inhibited by z-VAD.fmk, suggesting that caspases were responsible for the induction of apoptosis. Moreover, OTA triggered mitochondrial transmembrane potential (Deltachim) loss and caspase-9 and caspase-3 activation. Interestingly, Bcl-x(L) protein expression was decreased by OTA treatment, whereas Bcl-2 protein level was not affected. Down-regulation of bcl-x(L) mRNA was not observed in cells treated with OTA. Overexpression of Bcl-x(L) in Kit 225 cells protected them against mitochondrial perturbation and retarded the appearance of apoptotic cells. Taken together, our data indicate that mitochondria are a central component in OTA-induced apoptosis and that the loss of Bcl-x(L) may participate in OTA-induced cell death.
Assaf
Hind
H
INSERM UMR-S 461, Faculté de Pharmacie Paris XI, 5 rue J.-B. Clément, 92296 Châtenay-Malabry Cedex, France.
Azouri
Hayat
H
Pallardy
Marc
M
D000328:Adult; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D009183:Mycotoxins / Q000633:toxicity*; D009793:Ochratoxins / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D009183:Mycotoxins; D009793:Ochratoxins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C025589:ochratoxin A; D020169:Caspases