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 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.
Kim
Byeong-Mo
BM
School of Public Health, Seoul National University, 28 Yunkeun-dong, Seoul 110-460, Korea.
Chung
Hai-Won
HW
D000328:Adult; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000502:physiology*; D015153:Blotting, Western; D053181:Caspase 8 / Q000502:physiology*; D061945:Caspase Inhibitors; D002470:Cell Survival / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000187:drug effects* / Q000648:ultrastructure; D010835:Phytohemagglutinins / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D000975:Antioxidants; D051023:BH3 Interacting Domain Death Agonist Protein; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D010835:Phytohemagglutinins; D051028:bcl-2-Associated X Protein; D048051:p38 Mitogen-Activated Protein Kinases; D053181:Caspase 8; D003676:Deferoxamine