IL-1 induces its own gene expression in human PBMC, in cultured smooth muscle and in endothelial cells. IL-1-induced IL-1 may be part of a self-amplification or an autocrine growth factor in a variety of responses, and thus the endogenous regulation of IL-1 production likely contributes to the outcome of immunologic or inflammatory responses. In the present study, IFN-gamma consistently increased LPS-induced IL-1, but reduced the total amount of IL-1-induced IL-1 from PBMC. This reduction was observed in populations of adherent cells and cells selected with anti-Leu M3 antibody. On a molar basis, IFN-gamma and IFN-alpha 2 were equally effective in reducing IL-1-induced IL-1 synthesis. In PBMC of 24 human subjects, IFN-gamma also reduced PMA-induced IL-1 synthesis (67% decrease, p less than 0.001). The augmentation of LPS-stimulated IL-1 by IFN-gamma was observed only when added at the same time as LPS, but IFN-gamma could be added 6 h after stimulation with IL-1 and still suppress IL-1 production. LPS-induced mRNA for IL-1 beta was modestly enhanced by IFN-gamma whereas mRNA levels for TNF were markedly increased. In contrast, IFN-gamma suppressed mRNA accumulation for IL-beta after stimulation with IL-1 alpha by 60 to 95%. The addition of IFN-gamma 30 min before stimulation of PBMC with IL-1 suppressed IL-1 beta mRNA for up to 30 h. The half-life of IL-1 beta mRNA of approximately 2 h was not influenced by IFN-gamma. Thus, IFN-gamma reduces IL-1-induced IL-1 synthesis by suppressing IL-1-induced transcription, whereas the same concentrations of IFN-gamma augment LPS-induced IL-1 production by increasing transcription.