Rapamycin inhibits IL-1-mediated interferon-gamma production in the YAC-1 T cell lymphoma.

Rapamycin (RAP) exerts potent immunosuppressive effects that are thought to reflect primarily an inhibition of T cell proliferation driven by growth-promoting cytokines. In the present study, we examined whether RAP would be able to alter other T cell responses mediated by cytokines, such as lymphokine production. As a model system, we used the murine T cell lymphoma, YAC-1, that can be induced to produce IFN-gamma when activated with either ionomycin + PMA or IL-1 alpha + PMA. As previously found in other systems, induction of this lymphokine by ionomycin + PMA was not inhibited by RAP, although it was highly sensitive to inhibition by FK-506, an immunosuppressive macrolide structurally related to RAP. In contrast, the induction of the same lymphokine by IL-1 alpha + PMA was highly sensitive to RAP but resistant to FK-506. This inhibition of IFN-gamma production by RAP was detectable at the mRNA level. Such an inhibition was specific as it did not occur in a mutant clone selected for resistance to the antiproliferative effects of RAP. Moreover, kinetics analysis revealed that RAP still inhibited IFN-gamma mRNA accumulation in YAC-1 cells, when added as late as 12-18 h after initial stimulation of the cells with IL-1 alpha + PMA. While the inhibitory action of RAP could not be removed by extensive washing of the cells, it was readily reversed by a hundred-fold excess of FK-506 added to the cultures simultaneously with RAP or up to 16-18 h later. Altogether, these data indicate that the action of RAP in T cells is not limited to the inhibition of proliferation but also affects the regulation of lymphokine gene expression mediated by IL-1 alpha. The inhibition of lymphokine gene expression by RAP takes place at a late stage of the inductive response, and through a mechanism that involves interaction with the same cellular binding proteins as FK-506. Such an inhibitory effect of RAP may contribute significantly to its ability to suppress immune responses.