Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein-mediated cellular reactive oxygen species accumulation.
The mechanism of tumor necrosis factor (TNF)-induced nonapoptotic cell death is largely unknown, although the mechanism of TNF-induced apoptosis has been studied extensively. In wild-type mouse embryonic fibroblast cells under a caspase-inhibited condition, TNF effectively induced cell death that morphologically resembled necrosis. In this study, we utilized gene knockout mouse embryonic fibroblasts cells and found that tumor necrosis factor receptor (TNFR) I mediates TNF-induced necrotic cell death, and that RIP, FADD, and TRAF2 are critical components of the signaling cascade of this TNF-induced necrotic cell death. Inhibitors of NF-kappaB facilitated TNF-induced necrotic cell death, suggesting that NF-kappaB suppresses the necrotic cell death pathway. JNK, p38, and ERK activation seem not to be required for this type of cell death because mitogen-activated protein kinase inhibitors did not significantly affect TNF-induced necrotic cell death. In agreement with the previous reports that the reactive oxygen species (ROS) may play an important role in this type of cell death, the ROS scavenger butylated hydroxyanisole efficiently blocked TNF-induced necrotic cell death. Interestingly, during TNF-induced necrotic cell death, the cellular ROS level was significantly elevated in wild type, but not in RIP(-/-), TRAF2(-/-), and FADD(-/-) cells. These results suggest that RIP, TRAF2, and FADD are crucial in mediating ROS accumulation in TNF-induced necrotic cell death.
Lin
Yong
Y
Cell and Cancer Biology Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA. linyo@mail.nih.gov
Choksi
Swati
S
Shen
Han-Ming
HM
Yang
Qing-Feng
QF
Hur
Gang Min
GM
Kim
You Sun
YS
Tran
Jamie Hong
JH
Nedospasov
Sergei A
SA
Liu
Zheng-gang
ZG
D000818:Animals; D017209:Apoptosis; D029681:Arabidopsis Proteins / Q000378:metabolism*; D015153:Blotting, Western; D016923:Cell Death; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000166:cytology; D044943:Fatty Acid Desaturases / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D010957:Plasmids / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D029681:Arabidopsis Proteins; D016328:NF-kappa B; D011506:Proteins; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases