1 alpha,25-dihydroxyvitamin D3 transrepresses retinoic acid transcriptional activity via vitamin D receptor in myeloid cells.
Granulocytes and monocytes originate from a common committed progenitor cell. Commitment to either granulocytic or monocytic lineage is triggered by specific extracellular signals involving cytokines or nuclear receptor ligands (all-trans-retinoic acid (RA) and 1 alpha,25-dihydroxyvitamin D(3)). Here we show that the stimulatory effect of 1 alpha,25-dihydroxyvitamin D(3) on the production of monocytic colonies (CFU-M) is accompanied by a repression of granulocytic colony (CFU-G) production. We further demonstrate that in bipotent HL-60 myeloid cells as in purified human CD34+ myeloid progenitor cells, the 1 alpha,25-dihydroxyvitamin D(3)-induced monocytic differentiation is concomitant with a direct inhibition of the RA-transcriptional activity. Indeed, a transrepression of the RAR beta RA-target gene promoter via formation of a nuclear complex involving VDR was identified in vitro and in vivo. The fact that binding of RXR-RAR on DR3 is not observed suggests that contrary to RA-induced granulocytic differentiation, 1 alpha,25-dihydroxyvitamin D(3)-mediated monocytic differentiation requires positive and negative transcriptional controls both likely mediated by the RXR-VDR heterodimer. These novel findings implicate that 1 alpha,25-dihydroxyvitamin D(3) exerts a dominant negative effect on the RA-dependent granulocytic commitment of human bone marrow cells via repression of the RA-target gene promoters. Hence, the transcriptional response to RA and 1 alpha,25-dihydroxyvitamin D(3) in myeloid cells depends on a complex combinatory pattern of interaction among different nuclear receptors with DNA.
Laboratoire de Biologie Cellulaire Hématopoïétique, Institut National de la Santé et de la Recherche Médicale Equipe Mixte Inserm 00-03, Institut Universitaire d'Hématologie, Paris 7, Hôpital Saint-Louis, 75010 Paris, France.
Jean-Noël
JN
Bastie
Nicole
N
Balitrand
Fabien
F
Guidez
Isabelle
I
Guillemot
Jerome
J
Larghero
Cynthia
C
Calabresse
Christine
C
Chomienne
Laurent
L
Delva
D002117:Calcitriol / Q000494:pharmacology / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D018922:HL-60 Cells; D006801:Humans; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000502:physiology*; D020218:Response Elements / Q000235:genetics; D049230:Retinoid X Receptor beta / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology
D018167:Receptors, Calcitriol; D012097:Repressor Proteins; D049230:Retinoid X Receptor beta; D014212:Tretinoin; D008156:Luciferases; D002117:Calcitriol