TY - JOUR
T1 - A NF-κB/c-myc-dependent survival pathway is targeted by corticosteroids in immature thymocytes
AU - Wang, Weihong
AU - Wykrzykowska, Joanna
AU - Johnson, Todd
AU - Sen, Ranjan
AU - Sen, Jyoti
PY - 1999/1/1
Y1 - 1999/1/1
N2 - 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 IκBα and IκBβ in thymocytes and down-regulated NF-κB DNA binding activated by intrathymic signals. Down-regulation of NF-κB DNA binding preceded cell death, suggesting that NF-κB 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-κB induction diminished dexamethasone-induced death. Expression of the c-myc proto-oncogene, a NF- κB 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-κB/c-myc-dependent pathway in vivo.
AB - 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 IκBα and IκBβ in thymocytes and down-regulated NF-κB DNA binding activated by intrathymic signals. Down-regulation of NF-κB DNA binding preceded cell death, suggesting that NF-κB 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-κB induction diminished dexamethasone-induced death. Expression of the c-myc proto-oncogene, a NF- κB 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-κB/c-myc-dependent pathway in vivo.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0032963293&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/9886401
M3 - Article
C2 - 9886401
SN - 0022-1767
VL - 162
SP - 314
EP - 322
JO - Journal of immunology (Baltimore, Md.
JF - Journal of immunology (Baltimore, Md.
IS - 1
ER -