Baetu T M, Kwon H, Sharma S, Grandvaux N, Hiscott J
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, McGill University, Montreal, Canada.
J Immunol. 2001 Sep 15;167(6):3164-73. doi: 10.4049/jimmunol.167.6.3164.
The NF-kappaB family of transcription factors functions broadly in the host control of immunoregulatory gene expression, inflammation, and apoptosis. Using Jurkat T cells engineered to inducibly express a transdominant repressor of IkappaBalpha, we examined the role of NF-kappaB in the regulation of cytokine and apoptotic gene expression. In this T cell model, as well as in primary T lymphocytes, expression of TNF-related apoptosis-inducing ligand (TRAIL) apoptotic signaling protein was dramatically down-regulated by inhibition of NF-kappaB binding activity. TRAIL acts through membrane death receptors to induce apoptosis of activated T lymphocytes and can be up-regulated by a variety of physiological and pharmacological inducers. However, regulation of TRAIL gene expression has not been defined. Treatment with TCR mimetics (PMA/ionomycin, PHA, and anti-CD3/CD28 Abs) resulted in a rapid increase in the expression of TRAIL mRNA and cell surface TRAIL protein. Induction of the transdominant repressor of IkappaBalpha dramatically down-regulated surface expression of TRAIL, indicating an essential role for NF-kappaB in the regulation of TRAIL. The induced expression of TRAIL was linked to a c-Rel binding site in the proximal TRAIL promoter at position -256 to -265; mutation of this site or an adjacent kappaB site resulted in a complete loss of the inducibility of the TRAIL promoter. The regulation of TRAIL expression by NF-kappaB may represent a general mechanism that contributes to the control of TRAIL-mediated apoptosis in T lymphocytes.
转录因子NF-κB家族在宿主对免疫调节基因表达、炎症和细胞凋亡的控制中广泛发挥作用。我们利用经基因工程改造可诱导表达IkappaBalpha的反式显性阻遏物的Jurkat T细胞，研究了NF-κB在细胞因子和凋亡基因表达调控中的作用。在这个T细胞模型以及原代T淋巴细胞中，抑制NF-κB结合活性可显著下调肿瘤坏死因子相关凋亡诱导配体（TRAIL）凋亡信号蛋白的表达。TRAIL通过膜死亡受体发挥作用，诱导活化的T淋巴细胞凋亡，并且可被多种生理和药理诱导剂上调。然而，TRAIL基因表达的调控尚未明确。用TCR模拟物（佛波酯/离子霉素、植物血凝素和抗CD3/CD28抗体）处理导致TRAIL mRNA和细胞表面TRAIL蛋白的表达迅速增加。诱导表达IkappaBalpha的反式显性阻遏物可显著下调TRAIL的表面表达，表明NF-κB在TRAIL的调控中起重要作用。TRAIL的诱导表达与TRAIL启动子近端-256至-265位的c-Rel结合位点有关；该位点或相邻κB位点的突变导致TRAIL启动子诱导性完全丧失。NF-κB对TRAIL表达的调控可能代表一种普遍机制，有助于控制T淋巴细胞中TRAIL介导的凋亡。
