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m) and Cytochrome c Release Are Caspase Independent1
Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
CTLs kill targets by inducing them to die through apoptosis. A
number of morphological and biochemical events are now recognized as
characteristic features of the apoptotic program. Among these, the
disruption of the inner mitochondrial transmembrane potential
(
m) and the release of cytochrome c
into the cytoplasm appear to be early events in many systems, leading
to the activation of caspase-3 and, subsequently, nuclear apoptosis. We
show here that, in Jurkat targets treated in vitro with purified
granzyme B and perforin or granzyme B and adenovirus,
m collapse, reactive oxygen species production, and
cytochrome c release from mitochondria were observed.
Loss of m was also detected in an in vivo system
where green fluorescent protein-expressing targets were attacked by a
cytotoxic T cell line that kills predominantly through the granzyme
pathway. DNA fragmentation, phosphatidylserine externalization, and
reactive oxygen species production were inhibited in the presence of
the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl
ketone (zVAD-fmk) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl
ketone (zDEVD-fmk) in our in vitro system. Importantly, in either the
in vitro or in vivo systems, these inhibitors at concentrations up to
100 µM did not prevent m collapse. In addition,
cytochrome c release was observed in the in vitro system
in the absence or presence of zVAD-fmk. Thus the granzyme B-dependent
killing pathway in Jurkat targets involves mitochondrial alterations
that occur independently of caspases.
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