Caspase-Independent Phosphatidylserine Exposure During Apoptosis of Primary T Lymphocytes

Exposure of phosphatidylserine (PS) on the outer leaflet of the plasma membrane is a key feature of apoptosis. As the signals underlying these phenomena are unknown, it is generally assumed that PS exposure is a consequence of caspase activation, another hallmark of apoptosis. In this study we inves...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2002-11, Vol.169 (9), p.4805-4810
Main Authors: Ferraro-Peyret, Carole, Quemeneur, Laurence, Flacher, Monique, Revillard, Jean-Pierre, Genestier, Laurent
Format: Article
Language:English
Subjects:
Amino Acid Chloromethyl Ketones - pharmacology
Apoptosis - drug effects
Apoptosis - immunology
Caspase 3
Caspase 8
Caspase 9
Caspase Inhibitors
Caspases - metabolism
Caspases - physiology
Cell Nucleus - drug effects
Cell Nucleus - immunology
Cells, Cultured
DNA Fragmentation - drug effects
DNA Fragmentation - immunology
Enzyme Activation - drug effects
Enzyme Activation - immunology
Etoposide - pharmacology
Humans
Interleukin-2 - metabolism
Intracellular Membranes - drug effects
Intracellular Membranes - immunology
Intracellular Membranes - metabolism
Jurkat Cells
Kinetics
Membrane Potentials - drug effects
Membrane Potentials - immunology
Mitochondria - drug effects
Mitochondria - immunology
Mitochondria - metabolism
Permeability - drug effects
Phosphatidylserines - metabolism
Staurosporine - pharmacology
T-Lymphocyte Subsets - cytology
T-Lymphocyte Subsets - drug effects
T-Lymphocyte Subsets - enzymology
T-Lymphocyte Subsets - immunology
Tumor Cells, Cultured
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Summary:Exposure of phosphatidylserine (PS) on the outer leaflet of the plasma membrane is a key feature of apoptosis. As the signals underlying these phenomena are unknown, it is generally assumed that PS exposure is a consequence of caspase activation, another hallmark of apoptosis. In this study we investigated the role of caspases in PS externalization during apoptosis of activated PBL triggered by drugs (etoposide, staurosporine), CD95 engagement, or IL-2 withdrawal. Anti-CD95 mAb induces a rapid activation of caspases, followed by PS exposure and mitochondrial transmembrane potential (DeltaPsim) disruption. In contrast, etoposide (ETO), staurosporine (STS), or IL-2 withdrawal triggers concomitant caspase activation, PS exposure, and DeltaPsim disruption. Such kinetics suggest that PS exposure could be independent of caspase activation. As expected, in activated PBL treated by anti-CD95 mAb, the pan-caspase inhibitor Cbz-Val-Ala-Asp(OMe)-fluoromethylketone and the caspase-8 inhibitor Cbz-Leu-Glu-Thr-Asp(OMe)-fluoromethylketone, but not the caspase-9 inhibitor Cbz-Leu-Glu-His-Asp(OMe)-fluoromethylketone, inhibit PS externalization and DeltaPsim disruption. Surprisingly, during apoptosis induced by ETO, STS, or IL-2 withdrawal, none of those caspase inhibitors prevents PS externalization or DeltaPsim disruption, whereas they all inhibit DNA fragmentation as well as the morphological features of nuclear apoptosis. In Jurkat and H9 T cell lines, as opposed to activated PBL, PS exposure is inhibited by Cbz-Val-Ala-Asp(OMe)-fluoromethylketone during apoptosis induced by CD95 engagement, ETO, or STS. Thus, caspase-independent PS exposure occurs in primary T cells during apoptosis induced by stimuli that do not trigger death receptors.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.169.9.4805