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Laboratoire d’Immunopharmacologie, Institut National de la Santé et de la Recherche Médicale, Unité 503, Centre d’Etudes et de Recherche en Virologie et Immunologie, Lyon, France
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 (
m)
disruption. In contrast, etoposide (ETO), staurosporine (STS), or IL-2
withdrawal triggers concomitant caspase activation, PS exposure, and
m 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 m disruption. Surprisingly, during apoptosis
induced by ETO, STS, or IL-2 withdrawal, none of those caspase
inhibitors prevents PS externalization or m 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.
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