Notch-1 regulates NF-kappaB activity in hemopoietic progenitor cells

We investigated the interaction between two elements critical for differentiation of hemopoietic cells, the Notch-1 receptor and the transcription factor NF-kappaB. 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-kappaB-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-kappaB.