Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA.
Interferons enhance the cellular antiviral response by inducing expression of protective proteins. Many of these proteins are activated by dsRNA, a typical by-product of viral infection. Here we show that type-I and type-II interferons can sensitize cells to dsRNA-induced cytotoxicity. In caspase-8- or FADD-deficient Jurkat cells dsRNA induces necrosis, instead of apoptosis. In L929sA cells dsRNA-induced necrosis involves high reactive oxygen species production. The antioxidant butylated hydroxyanisole protects cells from necrosis, but shifts the response to apoptosis. Treatment with the caspase inhibitor benzyloxycarbonyl-Val-Ala-DL-Asp(OMe)-fluoromethylketone or overexpression of Bcl-2 prevent this shift and promote necrosis. Our results suggest that a single stimulus can initiate different death-signaling pathways, leading to either necrotic or apoptotic cell death. Inhibition of key events in these signaling pathways, such as caspase activation, cytochrome c release or mitochondrial reactive oxygen species production, tips the balance between necrosis and apoptosis, leading to dominance of one of these death programs.
Department of Molecular Biomedical Research, Unit of Molecular Signaling and Cell Death, Flanders Interuniversity Institute for Biotechnology and Ghent University, K.L. Ledeganckstraat 35, B-9000 Ghent, Belgium.
M
M
Kalai
G
G
Van Loo
T
T
Vanden Berghe
A
A
Meeus
W
W
Burm
X
X
Saelens
P
P
Vandenabeele
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053200:Fas-Associated Death Domain Protein; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology*; D019169:Jurkat Cells / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D051379:Mice; D009336:Necrosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012327:RNA Virus Infections / Q000188:drug therapy* / Q000235:genetics; D012328:RNA Viruses / Q000187:drug effects* / Q000235:genetics; D012330:RNA, Double-Stranded / Q000187:drug effects* / Q000235:genetics / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D012330:RNA, Double-Stranded; D017382:Reactive Oxygen Species; D002083:Butylated Hydroxyanisole; D016899:Interferon-beta; D007371:Interferon-gamma; D007372:Interferons; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases