Wang W, Wykrzykowska J, Johnson T, Sen R, Sen J
Rosenstiel Research Center and Department of Biology, Brandeis University, Waltham, MA 02254, USA.
J Immunol. 1999 Jan 1;162(1):314-22.
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.
糖皮质激素在体内调节T细胞成熟。虽然适当的T细胞发育需要低水平的激素，但在全身应激期间，高水平的糖皮质激素会将未成熟的发育中的胸腺细胞作为细胞死亡的靶点。在本报告中，我们提出了一种体内地塞米松诱导CD4+CD8+双阳性胸腺细胞凋亡的分子机制。地塞米松注射诱导胸腺细胞中IkappaBalpha和IkappaBbeta的表达，并下调由胸腺内信号激活的NF-kappaB DNA结合。NF-kappaB DNA结合的下调先于细胞死亡，这表明NF-kappaB可能对未成熟胸腺细胞的存活很重要。此外，用地塞米松对胸腺细胞单细胞悬液进行离体处理加速了p65/RelA的下调和细胞死亡。相反，NF-kappaB的诱导减少了地塞米松诱导的死亡。在接受地塞米松治疗的动物的胸腺细胞中，NF-kappaB靶标c-myc原癌基因的表达也降低了，并且在小鼠中c-myc的异位转基因表达部分挽救了双阳性胸腺细胞免于地塞米松介导的细胞死亡。这些观察结果表明，CD4+CD8+胸腺细胞的活力在体内可能由NF-kappaB/c-myc依赖性途径维持。
