Both IFN-b and TGF-b have demonstrated their ability to antagonize several of the stimulatory activities of IFN-g on human macrophages, thereby classifying them as Th2-like. Aiming at a further characterization of their role in Th1:Th2 development, we studied their possible interaction with IL-12, the key Th1 cytokine. We found that IFN-b by itself induced modest amounts of IFN-g, but was able to synergize with IL-12 for IFN-g induction. TGF-b, on the other hand, had no effect by itself and inhibited significantly the IL-12-induced IFN-g secretion. The differential effect of IFN-b and TGF-b on IL-12 bioactivity was most pronounced upon IFN-g synthesis, since IFN-b induced only marginal amounts of IL-10 and IL-12 and TGF-b diminished constitutive IL-10 production, while neither had a significant effect on TNF-a production. Although monocytes did not produce detectable IFN-g with any of the stimuli, adherent cells were found to cooperate with non-adherent lymphocytes for maximal IFN-g production. However, IL-18, a monocyte-derived IFN-g-inducing cytokine able to synergize with IL-12, was undetectable in IFN-b or IFN-b IL-12-stimulated cells. In conclusion, the ability of IFN-b to synergize with IL-12 for IFN-g synthesis, without significant concomitant IL-10 production, suggest a strong boost to Th1 development, which seems to be IL-18-independent.