Essential role of ICAM-1/LFA-1 interaction in synergistic effect of IL-18 and IL-12 on IFN-γ production in human PBMC

IL-18 (0-100 ng/ml) specifically upregulated ICAM-1 expression on monocytes in human PBMC as demonstrated in our previous study. In the present study, we examined whether the synergistic upregulation of ICAM-1 occurred after the stimulation with the combination of IL-18 and IL-12 and whether the synergistic production of IFN-gamma was dependent on the interaction between ICAM-1 on monocytes and LFA-1 on NK/T cells. The effect of IL-12 on ICAM-1 expression on monocytes was marginal even at the highest concentration (100 ng/ml). However, in the presence of IL-12 (100 ng/ml), the expression of ICAM-1 induced by IL-18 was significantly enhanced as compared with that obtained by IL-18 alone. In addition to the expression of ICAM-1 on monocytes, IFN-gamma production was synergistically stimulated by IL- 18 and IL-12. Anti-ICAM-1 and anti-LFA-1 Abs exhibited significant inhibitory effect on enhanced production of IFN-gamma by the combination of two cytokines, in particular, anti-ICAM-1 showing the complete inhibition. These results as a whole indicated that synergistic effect of IL-18 and IL-12 on IFN-gamma production in human PBMC is ascribed to the synergism of the effect of two cytokines on ICAM-1 expression on monocytes and that the subsequent ICAM-1/LFA-1 interaction plays an important role in the enhanced production of IFN-gamma.