TY - JOUR
T1 - 1α,25-dihydroxyvitamin D3-induced myeloid cell differentiation is regulated by a vitamin D receptor-phosphatidylinositol 3-kinase signaling complex
AU - Hmama, Zakaria
AU - Nandan, Devki
AU - Sly, Laura
AU - Knutson, Keith L.
AU - Herrera-Velit, Patricia
AU - Reiner, Neil E.
PY - 1999/12/6
Y1 - 1999/12/6
N2 - 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.
AB - 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.
KW - Differentiation
KW - Myeloid cell
KW - Phosphatidylinositol 3-kinase
KW - Vitamin D
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U2 - 10.1084/jem.190.11.1583
DO - 10.1084/jem.190.11.1583
M3 - Article
C2 - 10587349
AN - SCOPUS:0033233467
SN - 0022-1007
VL - 190
SP - 1583
EP - 1594
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 11
ER -