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.
Wang
W
W
Rosenstiel Research Center and Department of Biology, Brandeis University, Waltham, MA 02254, USA.
Wykrzykowska
J
J
Johnson
T
T
Sen
R
R
Sen
J
J
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D004247:DNA / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D016259:Genes, myc / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D016328:NF-kappa B; D003907:Dexamethasone; D004247:DNA