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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.

Activated human T cells via the CD2 or the CD3 pathways exhibited a higher capacity than resting T lymphocytes to incorporate and metabolize [3H]pafacether (paf) at 37 degrees C. Resting T lymphocytes lacked specific binding capacity for paf, yet high-affinity paf receptors (paf-R) were induced on CD3- or CD2-dependent activation. This up-regulation in the number of paf-R became apparent by day 1 of culture, reached a maximum of about 25,000 sites cell by days 4 to 6 and subsequently declined. Interestingly, human recombinant interleukin-2 in a dose-dependent manner prevented the decrease of high-affinity paf-R expression on T cells. By contrast, the receptor affinity was constant throughout the culture period. Thus, paf-R at different stages of T cell activation were indistinguishable with respect to receptor-ligand interaction, and differed only in their number. Together, these data demonstrate that after activation human T cells develop membrane high-affinity paf-binding sites. They also suggest for the first time that expression of the paf-R are coupled to T cell activation and/or differentiation.

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