The interaction of cytokines and their net balance with regard to macrophage activation (or deactivation) and immune stimulation (or suppression), ultimately determines the success of host-immune response at sites of active infection. A regulatory role for interleukin (IL)-12 in production of transforming growth factor (TGF)-beta1 has been suggested, however, remains controversial. In this study, we analyzed the effect of IL-12 on TGF-beta1 expression in the human lines, K562 and A549, and in primary human monocytes and macrophages. We found that IL-12 down-regulates TGF-beta1 mRNA expression in K562, monocytes and bone marrow cells, and to a lesser extent in the A549 cells. Using constructs containing different regions of the first promoter of the TGF-beta1 gene and a reporter gene, we also demonstrate that this effect is mediated through the TGF-beta1 gene promoter in the K562 and monocytic cell types. In conclusion, the critical role of IL-12 in the early activation of the immune response to pathogens may include down-modulation of TGF-beta1 gene activity.