Monocytes/macrophages and activated (but not resting) lymphocytes as well as certain subsets of thymocytes express the VDR. This protein is indistinguishable from the classical 50-kDa VDR and is encoded by an mRNA with identical nucleotide sequence to that of the human intestinal VDR. Acting via the VDR, 1,25(OH)2D3 modulates the production of a plethora of monocyte, lymphocyte, and bone marrow stromal cell products, including several interleukins and other cytokines, as well as various oncogenes and transcription factors. However, these hormonal effects vary depending on the signals used to activate blood mononuclear cells; moreover, each of the effects of the hormone can be either attenuated, abolished, or even reversed from negative to positive in the presence of phorbol esters. Lymphocytes also express a previously unrecognized 80-kDa cytosolic protein that shares immunologic cross-reactivity with the VDR. This protein is induced on activation and is downregulated by 1,25(OH)2D3, whereas the VDR is upregulated by 1,25(OH)2D3. In contrast to the signal-dependent effects of the hormone on cytokine production and lymphocyte proliferation, the effects of 1,25(OH)2D3 on the 80-kDa protein and VDR are independent of the activation signals. This apparent mechanistic distinction raises the possibility that the signal-independent effects of 1,25(OH)2D3 on the 80-kDa protein and the VDR might be due to direct interactions of the 1,25(OH)2D3-VDR complex with specific response elements (negative and positive VDREs, respectively) on these two genes; as opposed to the signal-dependent effects that might be due to influences of the 1,25(OH)2D3-VDR complex on other transcription factors that are generated in response to the different activation stimuli. Consistent with the second part of this contention, we have recently found that 1,25(OH)2D3 regulates the 50-kDa DNA binding subunit of the pleiotropic transcription factor NF-kappa B and the 105-kDa precursor of this subunit; as well as other members of the rel-related family of proteins, including v-rel and its normal cellular homolog c-rel, in activated normal human lymphocytes. Besides its influence on immune cell products, 1,25(OH)2D3 is a potent agent for the differentiation of cells of the myeloid lineage. In addition, 1,25(OH)2D3 stimulates the fusion and differentiation of hematopoietic progenitors into osteoclasts, an effect which accounts for the potent role of the hormone in bone resorption.(ABSTRACT TRUNCATED AT 400 WORDS)