International Immunology, Vol 10, 1807-1817, Copyright © 1998 by Oxford University Press
VN Ivanov and J Nikolic-Zugic
We characterized kinetic and biochemical changes during glucocorticoid
(GC)-induced apoptosis of immature CD8+CD4+ double-positive (DP)
thymocytes. A GC analog dexamethasone (Dex) induced rapid apoptotic
commitment and a transient up-regulation of the NF-kappaB/RelA-p50- binding
activity in DP cells. This required an early activation of proteasome, as
judged by the ability of a specific proteasomal inhibitor, lactacystine, to
delay apoptosis and to suppress Dex- dependent NF-kappaB activation.
Dex-induced apoptotic commitment was preceded by the rapid (3 h) cleavage
of both a typical caspase substrate, poly(ADP-ribose) polymerase (PARP),
and of nuclear transcription factors AP-1, NF-kappaB p50-p50 and NUR-77. By
contrast, phorbol myristate acetate (PMA) and/or ionomycin-induced
apoptosis had much slower kinetics, were preceded by an early increase of
NF- kappaB/RelA-p50, AP-1 and NUR-77 activities, and were insensitive to
proteasome inhibition. Both the transgenic Bcl-2 and zVAD-fmk, an inhibitor
of caspases, affected all features of Dex-induced apoptosis in a similar
fashion, by inhibiting cell death and PARP cleavage, and by stabilizing
AP-1, NF-kappaB p50-p50 and NUR-77 levels. Furthermore, Bcl-2 prevented
Dex-induced RelA-p50 activation. However, a higher gene dosage of the
transgenic Bcl-2 was required for protection against Dex, compared to the
PMA and/or ionomycin-induced apoptosis. These findings highlight the unique
mechanistic features of GC-induced apoptosis.
ARTICLES
Biochemical and kinetic characterization of the glucocorticoid-induced apoptosis of immature CD4+CD8+ thymocytes
Laboratory of T Cell Development, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
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