Thalidomide (Thal) was shown to be a potent immunomodulating agent. Because of their central role in controlling immunity, we investigated the effects of Thal on monocyte-derived dendritic cells (Mo-DC). The addition of 10 micro g/ml or 20 micro g/ml Thal from the beginning of monocyte culture with granulocyte macrophage-colony stimulating factor and interleukin (IL)-4 did not block Mo-DC differentiation. Moreover, Thal alone could not induce Mo-DC maturation. However, Thal exerted a modulation of Mo-DC functional properties. At 10 micro g/ml, Thal modified the allostimulatory capacity of DC little, whereas a dose of 20 micro g/ml up-regulated this capacity (P=.05) and increased IL-12p70 production in a dose-dependent manner between 10 and 20 micro g/ml (P=.001). Mo-DC generated with 10 micro g/ml Thal were poor stimulators of T helper cell type 1 (Th1) responses (P=.01), but 20 micro g/ml was able to strengthen Th1 responses (P=.03). Also, Thal induced a significant reduction of IL-10 production in response to the maturation-inducing stimulus CD40L. Similarly, tumor necrosis factor alpha production was significantly decreased when Mo-DC were exposed to 10 micro g/ml Thal, and a dose of 20 micro g/ml did not induce any significant changes. The effects of Thal in vitro on the secretion of IL-12p70 and strengthening of Th1 responses might contribute to the antitumor effects of Thal. Thus, DC appear to be potential targets for the immunomodulatory capacity of Thal, defining a new mechanism of action of this drug.