Notch-1 regulates NF-κB activity in hemopoietic progenitor cells
Notch-1 regulates NF-κB activity in hemopoietic progenitor cells
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DOI：
10.4049/jimmunol.167.8.4458
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发表时间：
2001-10-15
影响因子：
4.4
通讯作者：
Gabrilovich, DI
中科院分区：
文献类型：
--
作者：
Cheng, PY;Zlobin, A;Gabrilovich, DI
我们研究了造血细胞分化的两个关键因素，Notch-1受体和转录因子NF-κ B之间的相互作用。使用Notch-1反义转基因（Notch-AS-Tg）小鼠在造血祖细胞（HPC）中研究这些因子。在Notch-AS-Tg小鼠HPC中，NF-κ B的DNA结合及其激活转录的能力强烈降低。在用含有活化的Notch-1基因的逆转录病毒构建体转导细胞后，NF-κ B驱动的转录活性完全恢复。Notch-AS-Tg小鼠的HPC中NF-κ B家族的几个成员p65、p50、RelB和c-Rel的水平降低，这是由于基因表达下调。为了研究转基因小鼠中NF-κ B活性降低的功能后果，我们研究了LPS诱导的B细胞增殖和来自HPC的树突状细胞的GM-CSF依赖性分化。已知这两个过程密切依赖于NF-κ B。来自Notch-AS-Tg小鼠的B细胞对LPS的反应比从对照小鼠分离的B细胞低几乎3倍。Notch-AS-Tg小鼠树突状细胞的分化受到显著影响。然而，通过将活化的Notch-1转导到HPC中，它被恢复。总之，这些数据表明在HPC中NF-κ B活性通过NF-κ B的转录控制由Notch-1调节。
We investigated the interaction between two elements critical for differentiation of hemopoietic cells, the Notch-1 receptor and the transcription factor NF-KB. These factors were studied in hemopoietic progenitor cells (HPC) using Notch-1 antisense transgenic (Notch-AS-Tg) mice. DNA binding of NF-kappaB as well as its ability to activate transcription was strongly decreased in HPC from Notch-AS-Tg mice. NF-KB-driven transcriptional activity was completely restored after transduction of the cells with retroviral constructs containing activated Notch-1 gene. HPC from Notch-AS-Tg mice have decreased levels of several members of the NF-kappaB family, p65, p50, RelB, and c-Rel and this is due to down-regulation of the gene expression. To investigate functional consequences of decreased NF-kappaB activity in transgenic mice, we studied LPS-induced proliferation of B cells and GM-CSF-dependent differentiation of dendritic cells from HPC. These two processes are known to be closely dependent on NF-kappaB. B cells from Notch-AS-Tg mice had almost 3-fold lower response to LPS than B cells isolated from control mice. Differentiation of dendritic cells was significantly affected in Notch-AS-Tg mice. However, it was restored by transduction of activated Notch-1 into HPC. Taken together, these data indicate that in HPC NF-kappaB activity is regulated by Notch-1 via transcriptional control of NF-KB.