NF-κB activation induced by Notch ligand stimulation in acute myeloid leukemia cells

Abstract

There are conflicting reports regarding the effects of Notch activation on nuclear factor-kappaB (NF-kappaB) activity. The relationships are cell type-dependent and have not been fully elucidated. We examined the effects of Notch activation induced by a recombinant Notch ligand, Delta-like1 (Dll1), on the NF-kappaB activity in two acute myeloid leukemia (AML) cell lines. We found that Delta1-induced Notch activation activated the NF-kappaB pathway in THP-1 cells. Regarding the possible mechanisms, Dll1 stimulation increased the mRNA and protein expression levels of some components of the NF-kappaB pathway and induced phosphorylation of IKKalpha/beta, IkappaB and RelA proteins after 24 or 48 h of stimulation. Since the phosphorylation required a long time, it did not appear to be caused by physical interactions between Notch and NF-kappaB proteins, but rather by indirect effects. One possible mechanism for the indirect effects was the observed induction of IL-1beta expression by Dll1 stimulation. On the other hand, Notch activation did not affect NF-kappaB activity in TMD7 cells. RelA was phosphorylated without stimulation, indicating that NF-kappaB was constitutively activated in TMD7 cells. To the best of our knowledge, this is the first study to investigate AML cells and use a recombinant Notch ligand to activate Notch. The present findings lead to better understanding of Notch functions, which have not been fully elucidated.