IL-12, or cytotoxic lymphocyte maturation factor, is a recently cloned cytokine shown to influence lymphokine-activated killer cells activity in heterogeneous lymphocyte populations, proliferative activity as a costimulus in PBMC/PBL populations and IFN-gamma production in PBL. We have investigated the effects of IL-12 on immunomagnetically highly purified CD56+ lymphocytes, and compared the effects with those of IL-7 and IL-2. Our results show that IL-12 directly generated high lymphokine-activated killer cell activity in CD56+ NK cells, without the need for accessory cells. The IL-12-induced lymphokine-activated killer cell activity reached 50% of what was obtained with IL-2. In contrast, only low proliferative activity was induced by IL-12, as 10% of the IL-2-induced- and approximately 50% of the IL-7-induced proliferative activity was detected with IL-12. The CD56+ cells expressed high levels of IL-2R alpha and 75-kDa TNFR in response to IL-12, comparable to what was registered with IL-2 and IL-7. Furthermore, an extensive up-regulation of the CD56 Ag, to the level obtained with IL-2, was detected in the CD56+ NK cells in the presence of IL-12. Stimulation with IL-7 resulted in a more limited CD56 up-regulation in the CD56+ NK cells. Low concentrations of TNF-alpha were produced in response to both IL-12 and IL-7, with little or no TNF-beta production. Time course of the IL-2-induced TNF production revealed an initial TNF-alpha production, whereas significant levels of TNF-beta were detected after 72 h. The effects of both IL-12 and IL-7 on the CD56+ NK cells were inhibited by an anti-TNF-alpha mAb. Thus, IL-12 can directly influence NK cell activities in purified CD56+ cells, and endogenously produced TNF-alpha is involved in mediating the effects of both IL-12 and IL-7.