1alpha,25-dihydroxyvitamin D(3)-induced myeloid cell differentiation is regulated by a vitamin D receptor-phosphatidylinositol 3-kinase signaling complex.
1alpha,25-dihydroxyvitamin D(3) (D(3)) promotes the maturation of myeloid cells and surface expressions of CD14 and CD11b, markers of cell differentiation in response to D(3). To examine how these responses are regulated, THP-1 cells were grown in serum-free medium and incubated with D(3). This was associated with rapid and transient increases in phosphatidylinositol 3-kinase (PI 3-kinase) activity. Furthermore, induction of CD14 expression in response to D(3) 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 D(3) was also abrogated by LY294002 and wortmannin. Similarly, LY294002 and wortmannin inhibited D(3)-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 D(3)-induced monocyte differentiation, independent of any effects on p21.
Hmama
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Department of Medicine, The University of British Columbia, Faculties of Medicine and Science, The Research Institute of the Vancouver Hospital and Health Sciences Center, Vancouver, British Columbia, Canada.
Nandan
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Sly
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Knutson
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KL
Herrera-Velit
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Reiner
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D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D002117:Calcitriol / Q000494:pharmacology*; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000235:genetics*; D016177:Macrophage-1 Antigen / Q000235:genetics; D009000:Monocytes / Q000276:immunology*; D009025:Morpholines / Q000494:pharmacology; D016296:Mutagenesis; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D018167:Receptors, Calcitriol / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D000077191:Wortmannin
D000730:Androstadienes; D015703:Antigens, CD; D002867:Chromones; D004791:Enzyme Inhibitors; D018950:Lipopolysaccharide Receptors; D016177:Macrophage-1 Antigen; D009025:Morpholines; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D011994:Recombinant Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D002117:Calcitriol; D000077191:Wortmannin