Desferrioxamine (DFX) induces apoptosis through the p38-caspase8-Bid-Bax pathway in PHA-stimulated human lymphocytes

Desferrioxamine (DFX) induces apoptosis in human lymphocytes, although the mechanism leading to cell death is unclear. Therefore, we investigated the signaling pathways implicated in DFX-induced apoptosis in lymphocytes. DFX treatment activated caspase-9, caspase-3, and caspase-8. DFX-induced apopto...

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Bibliographic Details
Published in:Toxicology and applied pharmacology 2008-04, Vol.228 (1), p.24-31
Main Authors: Kim, Byeong-Mo, Chung, Hai-Won
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Adult
Antioxidant
ANTIOXIDANTS
Antioxidants - pharmacology
APOPTOSIS
Apoptosis - drug effects
bcl-2-Associated X Protein - drug effects
bcl-2-Associated X Protein - physiology
BH3 Interacting Domain Death Agonist Protein - physiology
Biological and medical sciences
Blotting, Western
Caspase 8 - physiology
Caspase Inhibitors
Cell death mechanisms
Cell Survival - drug effects
CLEAVAGE
Deferoxamine - pharmacology
Enzyme Inhibitors - pharmacology
Humans
In Vitro Techniques
Inhibitors
LYMPHOCYTES
Lymphocytes - drug effects
Lymphocytes - ultrastructure
Medical sciences
Mitogen-activated protein kinases (MAPKs)
p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases - physiology
PHOSPHORYLATION
PHOSPHOTRANSFERASES
Phytohemagglutinins - pharmacology
PROPOSALS
Protein Conformation - drug effects
Signal Transduction - drug effects
Toxicology
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Summary:Desferrioxamine (DFX) induces apoptosis in human lymphocytes, although the mechanism leading to cell death is unclear. Therefore, we investigated the signaling pathways implicated in DFX-induced apoptosis in lymphocytes. DFX treatment activated caspase-9, caspase-3, and caspase-8. DFX-induced apoptosis was inhibited by both z-IETD-fmk and z-DEVD-fmk. DFX treatment also enhanced caspase-8 activity, Bid cleavage, and the conformational activation of Bax. DFX treatment activated two MAPKs, p38 and JNK, and induced the phosphorylation of two proteins in the p38 pathway, MKK3 and MKK6. DFX treatment also increased the phosphorylation of two downstream targets of p38, ATF-2 and MAPKAPK2, indicating that DFX promotes p38 activity. In addition, the selective p38 inhibitor SB203580 suppressed DFX-induced apoptosis and caspase-8 activation, whereas the JNK inhibitor, SP600125, and the ERK inhibitor, PD98059, had no effect. Our results suggest that DFX-induced apoptosis is mediated by the p38 pathway and a caspase-8-dependent Bid-Bax pathway in human lymphocytes.
ISSN:0041-008X
1096-0333
DOI:10.1016/j.taap.2007.11.022