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 level s of hormones are required for appropriate T cell development, high levels of glucocorticoid hormones target immature developing thymocytes for cell d eath during systemic stress. In this report, we propose a molecular mechani sm for the induction of apoptosis in CD4(+)CD8(+) double-positive thymocyte s by dexamethasone in vivo, Dexamethasone injection induced the expression of I kappa B alpha: and I kappa B beta in thymocytes and down-regulated NF- kappa B DNA binding activated by intrathymic signals, Down-regulation of NF -kappa B DNA binding preceded cell death, suggesting that NF-kappa B may be important for the survival of immature thymocytes. In addition, ex vivo tr eatment of thymocyte single-cell suspension with dexamethasone, accelerated p65/RelA down-regulation and cell death. Conversely, NF-kappa B induction diminished dexamethasone-induced death. Expression of the c-myc proto-oncog ene, a NF-kappa B target, was also reduced in thymocytes of dexamethasone-t reated animals, and ectopic transgenic expression of c-myc in mice provided partial rescue of double-positive thymocytes from dexamethasone mediated c ell death, These observations suggest that viability of CD4(+)CD8(+) thymoc ytes may be maintained by an NF-kappa B/c-myc-dependent pathway in vivo.