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Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA

par Kalai, Michaël ;Van Loo, Geert;Vanden Berghe, Tom;Meeus, Ann;Burm, W.;Saelens, Xavier;Vandenabeele, Peter
Référence Cell death and differentiation, 9, 9, page (981-994)
Publication Publié, 2002-09

Article révisé par les pairs

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Résumé :

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 ot Bcl-2 prevent this shift and promote necrosis. Our results suggest that a single stimulus can initiate different death-signaling pathways, leading to either necroticor 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 apoptoslis, leading to dominance of one of these death programs.