A NF-kappa B/c-myc-dependent survival pathway is targeted by corticosteroids in immature thymocytes.
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 IkappaBalpha and IkappaBbeta in thymocytes and down-regulated NF-kappaB DNA binding activated by intrathymic signals. Down-regulation of NF-kappaB DNA binding preceded cell death, suggesting that NF-kappaB 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-kappaB induction diminished dexamethasone-induced death. Expression of the c-myc proto-oncogene, a NF-kappaB 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-kappaB/c-myc-dependent pathway in vivo.