The 1alpha,25-dihydroxyvitamin D(3) (1,25- [OH](2)VD(3)) modulates the differentiation of monocytic cell lines and monocytes (MOs) in vitro. Up to now several target genes of 1,25(OH)(2)VD(3) have been described in monocytic cell lines; however, little is known about target genes in primary MOs. With the Differential Display technique, we found a transcript up-regulated by 1,25(OH)(2)VD(3) in short-term cultured human blood MOs, which we called MADDAM (metalloprotease and disintegrin dendritic antigen marker; EMBL/GenBank/DDBJ accession no. Y13786). Northern blot analysis confirmed this result and revealed a signal of MADDAM messenger RNA (mRNA) at about 7.5 kilobases (kb). Long-term culture (more than 20 hours) of MOs during macrophage (MAC) differentiation led to a rapid and complete down-regulation of MADDAM expression. In contrast, MADDAM expression was maintained in MOs differentiated along the dendritic cell (DC) pathway and induced in CD34(+)-derived DCs. In addition, in situ hybridization revealed signals of MADDAM mRNA in follicles of human lymph nodes and MADDAM mRNA was detected in freshly isolated human blood-DCs by reverse transcription-polymerase chain reaction (RT-PCR). By means of a database search, we found that MADDAM is a member of the ADAM (a metalloprotease and disintegrin) family, the human homologue to murine meltrin-beta (ADAM 19). From these data, we conclude that MADDAM is an important marker for the differentiation and characterization of DCs and the distinction between MACs and DCs. (Blood. 2000;96:732-739)