Kalai M, Van Loo G, Vanden Berghe T, Meeus A, Burm W, Saelens X, Vandenabeele P
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.
Cell Death Differ. 2002 Sep;9(9):981-94. doi: 10.1038/sj.cdd.4401051.
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.
干扰素通过诱导保护性蛋白的表达来增强细胞的抗病毒反应。这些蛋白中的许多都由双链RNA激活，双链RNA是病毒感染的典型副产物。在此我们表明，I型和II型干扰素可使细胞对双链RNA诱导的细胞毒性敏感。在缺乏半胱天冬酶-8或FADD的Jurkat细胞中，双链RNA诱导坏死而非凋亡。在L929sA细胞中，双链RNA诱导的坏死涉及高活性氧的产生。抗氧化剂丁基羟基茴香醚可保护细胞免于坏死，但会使反应转向凋亡。用半胱天冬酶抑制剂苄氧羰基-Val-Ala-DL-Asp(OMe)-氟甲基酮处理或Bcl-2的过表达可防止这种转变并促进坏死。我们的结果表明，单一刺激可启动不同的死亡信号通路，导致坏死性或凋亡性细胞死亡。抑制这些信号通路中的关键事件，如半胱天冬酶激活、细胞色素c释放或线粒体活性氧的产生，会打破坏死与凋亡之间的平衡，导致其中一种死亡程序占主导。
