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Caspase-dependent initiation of apoptosis and necrosis by the Fas receptor in lymphoid cells: onset of necrosis is associated with delayed ceramide increase
Claudio A. Hetz1,
Lisette Leyton1, and
Andrew F. G. Quest1,*
1 Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de
Chile, Santiago, Chile 2 Institute of Biochemistry, University of Lausanne, Switzerland
Author for correspondence
Accepted for publication 4 September 2002.
Engagement of the Fas receptor promotes apoptosis by activationof
caspases. In addition, alterations in plasma membrane lipidorientation and
intracellular ceramide levels are often observed.In A20 B-lymphoma cells,
FasL-induced cell death and phosphatidylserine(PS) externalization were
completely prevented by the genericcaspase inhibitor z-VAD-fmk. By contrast,
the caspase-3 inhibitorAc-DEVD-cho only partially restored cell viability and
had noeffect on surface exposure of PS. Flow cytometric analysis afterFasL
treatment identified two populations of dead cells. Inone, death was
dependent on caspase-3 and paralleled by DNAfragmentation and cell shrinkage.
In the second, death occurredin the absence of caspase-3 activity and
apoptotic featuresbut was also blocked by zVAD-fmk. By morphological criteria
thesewere identified as apoptotic and necrotic cells, respectively.Using
fluorescent substrates, caspase-3 activity was detectedonly in the apoptotic
cell population, whereas caspase-8 activitywas detected in both. Both forms
of caspase-8-dependent celldeath were also detected downstream of Fas in
Jurkat T-cells,where Fas-dependent PS externalization and delayed ceramide
production,which is similar to results shown here in A20 cells, have been
reported.However, for Raji B-cells, lacking lipid scrambling and ceramide
productionin response to Fas activation, only apoptosis was detected.
Short-chainC2- or C6-ceramides, but not the respective inactive dihydro
compoundsor treatment with bacterial sphingomyelinase, induced predominantly
necroticrather than apoptotic cell death in A20 B-, Raji B- and Jurkat
T-cells.Thus, delayed elevation of ceramide is proposed to promote necrosis
inthose Fas-stimulated cells where caspase-8 activation was insufficientto
trigger caspase-3-dependent apoptosis.
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Biological Roles of Acid and Neutral Sphingomyelinases and Their Regulation by Nitric Oxide.