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Plasmid DNA (pDNA) uptake and subsequent cellular activation characteristics were studied in three types of human monocyte-derived cells, that is, human monocytes, macrophages, and dendritic cells (DCs) in primary culture. Naked pDNA was bound to and taken up by the macrophages and DCs while only significant binding occurred in the monocytes. pDNA binding to these monocyte-derived cells was significantly inhibited by polyinosinic acid (poly[I]), dextran sulfate, maleylated bovine serum albumin (Mal-BSA) and to a lesser extent by polycytidylic acid (poly[C]), but not by dextran or galactosylated BSA (Gal-BSA), mannosylated BSA (Man-BSA), suggesting that a specific mechanism for polyanions is involved in the pDNA binding. In cellular activation studies, naked pDNA could not induce TNF-alpha production from any monocyte-derived cells, regardless of the abundant presence of CpG motifs in the pDNA. However, when complexed with cationic liposomes, pDNA produced a significant amount of TNF-alpha from the human macrophages. TNF-alpha induction was not observed in the monocytes or DCs. Moreover, calf thymus DNA (CT DNA) complexed with cationic liposomes also induced TNF-alpha production to a similar extent in the human macrophages. These results indicate that, among human monocyte-derived cells, macrophages are activated by DNA when complexed with cationic liposomes in a CpG motif-independent manner.