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A NF-B/c-myc-Dependent Survival Pathway Is Targeted by Corticosteroids in Immature Thymocytes¹

Weihong Wang^*, Joanna Wykrzykowska, Todd Johnson, Ranjan Sen^* and Jyoti Sen^2,

^* 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 IB 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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