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Inhibition of caspase activity induces a switch from apoptosis to necrosis
C Lemaire1, K Andréau, V Souvannavong
1Institut de Biochimie, CNRS ERS 0571, Université Paris-Sud, Orsay, France. christophe.lemaire@bbmpc.u-psud.fr
Abstract:
The role of caspases in B lymphocyte cell death was investigated by using two broad spectrum inhibitors of the caspase family, Z-Asp-cmk and Z-VAD-fmk. They totally prevented spontaneous and drug-induced apoptosis and inhibited the CPP32/caspase-3-like activity exhibited by apoptotic cells. However, the suppression of apoptosis was not associated with a long-term increase of cell survival, but conversely, with a switch from apoptotic death to the necrotic form. These results strongly suggest that apoptosis and necrosis share common initiation pathways, the final issue being determined by the presence of an active caspase.
Insights
Caspase inhibitors blocked B cell apoptosis but led to necrosis, suggesting shared pathways. Active caspases determine cell death type, impacting lymphocyte survival.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Caspases are key mediators of programmed cell death (apoptosis).
- B lymphocytes undergo apoptosis as a critical process in immune regulation.
- The precise role of caspases in determining cell death pathways (apoptosis vs. necrosis) in B cells requires further elucidation.
Purpose of the Study:
- To investigate the role of caspases in B lymphocyte cell death.
- To determine if caspase inhibition alters the mode of cell death from apoptosis to necrosis.
- To explore the relationship between caspase activity and cell death pathways.
Main Methods:
- Utilized broad-spectrum caspase inhibitors (Z-Asp-cmk and Z-VAD-fmk) in B lymphocyte cultures.
- Assessed spontaneous and drug-induced apoptosis.
- Measured CPP32/caspase-3-like activity in apoptotic cells.
- Observed cell survival and death morphology (apoptosis vs. necrosis).
Main Results:
- Caspase inhibitors completely prevented spontaneous and drug-induced apoptosis in B lymphocytes.
- Inhibitors suppressed CPP32/caspase-3-like activity.
- Suppression of apoptosis resulted in a switch to necrotic cell death, not increased survival.
- Necrotic cell death was observed instead of apoptosis upon caspase inhibition.
Conclusions:
- Caspase activity is essential for executing apoptosis in B lymphocytes.
- Apoptosis and necrosis share common initiation pathways in B cells.
- The presence of active caspases dictates whether a cell undergoes apoptosis or necrosis.