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Rapamycin inhibits IL-1-mediated interferon-gamma production in the YAC-1 T cell lymphoma
1Department of Immunology, Merck Research Laboratories, Rahway, New Jersey 07065.
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.
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.