1α,25-dihydroxyvitamin D3-induced myeloid cell differentiation is regulated by a vitamin D receptor-phosphatidylinositol 3-kinase signaling complex

Zakaria Hmama, Devki Nandan, Laura Sly, Keith L. Knutson, Patricia Herrera-Velit, Neil E. Reiner

Research output: Contribution to journalArticlepeer-review

151 Scopus citations

Abstract

1α,25-dihydroxyvitamin D3 (D3) promotes the maturation of myeloid cells and surface expressions of CD14 and CD11b, markers of cell differentiation in response to D3. To examine how these responses are regulated, THP-1 cells were grown in serum-free medium and incubated with D3. This was associated with rapid and transient increases in phosphatidylinositol 3-kinase (PI 3-kinase) activity. Furthermore, induction of CD14 expression in response to D3 was abrogated by (a) the PI 3-kinase inhibitors LY294002 and wortmannin; (b) antisense oligonucleotides to mRNA for the p110 catalytic subunit of PI 3-kinase; and (c) a dominant negative mutant of PI 3-kinase. In THP-1 cells, induction of CD11b expression by D3 was also abrogated by LY294002 and wortmannin. Similarly, LY294002 and wortmannin inhibited D3-induced expression of both CD14 and CD11b in peripheral blood monocytes. In contrast to CD14 and CD11b, hormone-induced expression of the Cdk inhibitor p21 in THP-1 cells was unaffected by either wortmannin or LY294002. These findings suggest that PI 3-kinase selectively regulates D3-induced monocyte differentiation, independent of any effects on p21. Pretreatment of THP-1 cells with antisense oligonucleotides to the vitamin D receptor (VDR) mRNA abrogated both activation of PI 3-kinase in response to D3 and hormone-induced CD14 expression. Moreover, both Western blots and in vitro kinase assays carried out on immunoprecipitates of the VDR showed that D3 treatment brought about formation of a complex containing both PI 3-kinase and the VDR. These findings reveal a novel, nongenomic mechanism of hormone action regulating monocyte differentiation, in which vitamin D3 activates a VDR- and PI 3-kinase-dependent signaling pathway.

Original languageEnglish (US)
Pages (from-to)1583-1594
Number of pages12
JournalJournal of Experimental Medicine
Volume190
Issue number11
DOIs
StatePublished - Dec 6 1999

Keywords

  • Differentiation
  • Myeloid cell
  • Phosphatidylinositol 3-kinase
  • Vitamin D

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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