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*
Department of Immunology, University of Glasgow, Glasgow, United Kingdom; and
Centre for Rheumatic Diseases, Royal Infirmary, Glasgow, United Kingdom
Cross-linking of the Ag receptors on the immature B cell lymphoma,
WEHI-231, leads to growth arrest and apoptosis. We now show that
although commitment to such B cell receptor (BCR)-mediated apoptosis
correlates with mitochondrial phospholipase A2 activation,
disruption of mitochondrial function, and ATP depletion, it is executed
independently of caspase activation. First, we demonstrate a pivotal
role for mitochondrial function in determining B cell fate by showing
up-regulation of cytosolic phospholipase A2 expression,
induction of mitochondrial phospholipase A2 activity,
arachidonic acid-mediated collapse of mitochondrial transmembrane inner
potential (
m), and depletion of cellular ATP under
conditions of apoptotic, but not proliferative, signaling via the BCR.
Importantly, disruption of m, ATP depletion, and
apoptosis can be prevented by rescue signals via CD40 or by
m stabilizers such as antimycin or oligomycin.
Second, we show that commitment and postmitochondrial execution of
BCR-mediated apoptosis are not dependent on caspase activation by
demonstrating that such apoptotic signaling does not induce release of
cytochrome c from the mitochondria or activation of
effector caspases, as evidenced by poly(ADP-ribose) polymerase or
Bcl-xL cleavage. Indeed, apoptotic signaling via the BCR in
WEHI-231 B cells does not stimulate the activation of caspase-3 and,
consistent with this, BCR-mediated disruption of m
and commitment to apoptosis take place in the presence of caspase
inhibitors. In contrast, BCR signaling induces the postmitochondrial
activation of cathepsin B, and resultant apoptosis is blocked by the
cathepsin B inhibitor,
(23,35)trans-epoxysuccinyl-L-leucylamindo-3-methylbutane
ethyl ester (EST) suggesting a key role for this executioner protease
in Ag receptor-driven apoptosis of WEHI-231 immature B
cells.
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