Activation of the CD95 death receptor as well as ionizing radiation induces
apoptotic cell death in human lymphoma cells. The activation of caspases i
s a hallmark of apoptosis induction irrespective of the apoptotic trigger.
In contrast to death receptor signaling, the exact mechanisms of radiation-
induced caspase activation are not well understood. We provide evidence tha
t both, radiation and CD95 stimulation, induce the rapid activation of casp
ase-8 and BID followed by apoptosis in Jurkat T-cells, To analyse the relat
ive position of caspase-8 within the apoptotic cascade we studied caspase a
ctivation and apoptosis in Jurkat cells overexpressing Bcl-2 or Bcl-x(L). C
aspase-8 activation, proapoptotic BID cleavage and apoptosis in response to
radiation were abrogated in these cells, while the responses to CD95 stimu
lation were only partially attenuated by overexpression of Bcl-2 family mem
bers. In parallel, the breakdown of the mitochondrial transmembrane potenti
al (Delta Psi(m),) in response to radiation was inhibited by overexpression
of Bcl-2/Bcl-x(L) Jurkat cells genetically deficient for caspase-8 were fo
und to be completely resistant towards CD95, However, radiation-induced apo
ptotic responses in caspase-8-negative cells displayed only a modest reduct
ion. We conclude that ionizing radiation activates caspase-8 and BID downst
ream of mitochondrial damage suggesting that, in contrast to CD95, both eve
nts function as executioners rather than initiators of the apoptotic proces
s.