Matrix metalloproteinase-12 (MMP-18) has been shown to play critical roles in atherogenesis. To determine the cellular mechanisms for control of MMP-12 expression, we studied the effects of several cytokines (GM-CSF, IL-1 beta, MCP-1) and CD40 ligand on MMP-12 expression in human monocyte/macrophages. Undifferentiated U937 monocytic cells and human peripheral blood monocytes did not express MMP-12. However, in the presence of GM-CSF, these monocytes showed MMP-12 expression at both the transcriptional and protein levels. The combination of treatment with GM-CSF and IL-1 beta or MCP-1 resulted in a further increase of MMP-1S expression compared to treatment with GM-CSF alone. By contrast, both U937-derived macrophages and human peripheral blood monocyte-derived macrophages showed spontaneous MMP-1S expression, which was significantly increased by the addition of either GM-CSF or anti-CD40Ab. These results indicate that expression of MMP-12 is dependent upon the state of cellular differentiation and enhanced by cytokines and CD40 signaling.