1,25-Dihydroxyvitamin D3 induces biphasic NF-κB responses during HL-60 leukemia cells differentiation through protein induction and PI3K/Akt-dependent phosphorylation/degradation of IκB

Anfernee K W TSE, Chi Keung Wan, Xiao Ling Shen, Guo Yuan Zhu, Hon Yeung Cheung, Mengsu Yang, David W F FONG*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

1,25-Dihydroxyvitamin D3 (VD3) induces differentiation in a number of leukemia cell lines and under various conditions is able to either stimulate or inhibit nuclear factor kappa B (NF-κB) activity. Here we report a time-dependent biphasic regulation of NF-κB in VD3-treated HL-60 leukemia cells. After VD3 treatment there was an early ∼ 4 h suppression and a late 8-72 h prolonged reactivation of NF-κB. The reactivation of NF-κB was concomitant with increased IKK activities, IKK-mediated IκBα phosphorylation, p65 phosphorylation at residues S276 and S536, p65 nuclear translocation and p65 recruitment to the NF-κB/vitamin D responsive element promoters. In parallel with NF-κB stimulation, there was an up-regulation of NF-κB controlled inflammatory and anti-apoptotic genes such as TNFα, IL-1β and Bcl-xL. VD3-triggered reactivation of NF-κB was associated with PI3K/Akt phosphorylation. PI3K/Akt antagonists suppressed VD3-stimulated IκBα phosphorylation as well as NF-κB-controlled gene expression. The early ∼ 4 h VD3-mediated NF-κB suppression coincided with a prolonged increase of IκBα protein which require de novo protein synthesis, lasted for as least 72 h and was insensitive to MAPK, IKK or PI3K/Akt inhibitors. Our data suggest a novel biphasic regulation of NF-κB in VD3-treated leukemia cells and our results may have provided the first molecular explanation for the contradictory observations reported on VD3-mediated immune-regulation.

Original languageEnglish
Pages (from-to)1722-1734
Number of pages13
JournalExperimental Cell Research
Volume313
Issue number8
DOIs
Publication statusPublished - 1 May 2007

Scopus Subject Areas

  • Cell Biology

User-Defined Keywords

  • 1,25-Dihydroxyvitamin D
  • IKK
  • Leukemia
  • Monocytic differentiation
  • NF-κB

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