Interferon (IFN) regulatory factor (IRF)-4 is a lymphoid- and myeloid-restricted transcription factor of the IRF family. We analyzed its expression during differentiation of human monocytes along the macrophage or the dendritic cell (DC) pathway and in blood myeloid and plasmacytoid DC (M-DC and P-DC, respectively) subsets. Monocyte differentiation into DC, driven by granulocyte macrophage-colony stimulating factor (GM-CSF)/interleukin-4 or GM-CSF/IFN-beta, resulted in a strong up-regulation of IRF-4 mRNA and protein, which was further increased by lipopolysaccharide. It is interesting that 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], a potent inhibitor of DC differentiation, completely abolished IRF-4 up-regulation. IRF-4 was also detected in blood P-DC and M-DC. However, up-regulation upon in vitro culture and down-regulation by 1,25(OH)(2)D(3) was observed in M-DC but not in P-DC. These results point to IRF-4 as a potential player in human myeloid DC differentiation and as a novel target for the immunomodulatory activity of 1,25(OH)(2)D(3).