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B/c-myc-Dependent Survival Pathway Is Targeted by Corticosteroids in Immature Thymocytes1
*
Rosenstiel Research Center and Department of Biology, Brandeis University, Waltham, MA 02254; and
Dana-Farber Cancer Institute, Boston, MA 02115
Glucocorticoid hormones modulate T cell maturation in vivo. While
low levels of hormones are required for appropriate T cell development,
high levels of glucocorticoid hormones target immature developing
thymocytes for cell death during systemic stress. In this report, we
propose a molecular mechanism for the induction of apoptosis in
CD4+CD8+ double-positive thymocytes by
dexamethasone in vivo. Dexamethasone injection induced the expression
of I
B
and IBß in thymocytes and down-regulated NF-B DNA
binding activated by intrathymic signals. Down-regulation of NF-B
DNA binding preceded cell death, suggesting that NF-B may be
important for the survival of immature thymocytes. In addition, ex vivo
treatment of thymocyte single-cell suspension with dexamethasone
accelerated p65/RelA down-regulation and cell death. Conversely,
NF-B induction diminished dexamethasone-induced death. Expression of
the c-myc proto-oncogene, a NF-B target, was also
reduced in thymocytes of dexamethasone-treated animals, and ectopic
transgenic expression of c-myc in mice provided partial
rescue of double-positive thymocytes from dexamethasone mediated cell
death. These observations suggest that viability of
CD4+CD8+ thymocytes may be maintained by an
NF-B/c-myc-dependent pathway in
vivo.
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