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Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA
M Kalai1, G Van Loo, T Vanden Berghe
1Department 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.
Abstract:
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.
Insights
Interferons prime cells for dsRNA-induced cell death. Interferons can sensitize cells to dsRNA, influencing whether cells undergo apoptosis or necrosis based on signaling pathway modulation.
Area of Science:
- Immunology
- Cell Biology
- Virology
Background:
- Interferons (IFNs) bolster cellular antiviral defenses by upregulating protective proteins, often activated by double-stranded RNA (dsRNA).
- dsRNA is a common viral infection byproduct, triggering cellular responses.
- The precise outcomes of dsRNA exposure, particularly concerning cell death pathways, remain areas of active investigation.
Purpose of the Study:
- To investigate how type-I and type-II interferons influence cellular sensitivity to dsRNA-induced cytotoxicity.
- To elucidate the signaling pathways governing dsRNA-induced apoptosis versus necrosis.
- To identify key molecular regulators that dictate the balance between these cell death programs.
Main Methods:
- Utilized Jurkat cells deficient in caspase-8 or FADD to assess dsRNA-induced cell death mechanisms.
- Employed L929sA cells to study the role of reactive oxygen species (ROS) in dsRNA-induced necrosis.
- Administered the antioxidant butylated hydroxyanisole (BHA) and employed caspase inhibitors or Bcl-2 overexpression to modulate cell death pathways.
Main Results:
- Type-I and type-II interferons sensitize cells to dsRNA-induced cytotoxicity.
- In caspase-8/FADD-deficient cells, dsRNA triggers necrosis, not apoptosis.
- dsRNA-induced necrosis in L929sA cells involves significant ROS production; BHA mitigates necrosis but induces apoptosis.
- Caspase inhibition or Bcl-2 overexpression promotes necrosis, preventing the shift to apoptosis.
Conclusions:
- A single stimulus, dsRNA, can activate distinct cell death signaling pathways, leading to either necrosis or apoptosis.
- Modulation of key signaling events, including caspase activation, cytochrome c release, and mitochondrial ROS production, determines the cell's fate.
- Interferon priming significantly impacts the cellular response to dsRNA, shifting the balance towards specific death pathways.
