SUPPRESSION OF ADULT T-CELL LEUKEMIA-DERIVED FACTOR HUMAN THIOREDOXIN INDUCTION BY FK506 AND CYCLOSPORINE-A - A NEW MECHANISM OF IMMUNE MODULATION VIA REDOX CONTROL

Adult T cell leukemia-derived factor (ADF), which is identical to a disulfide reducing enzyme human thioredoxin (TRX), is produced and released by activated or virus-infected lymphocytes. Here we report that, in peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin (PHA), ADF/TRX mRNA was induced within 8 h after stimulation as detected by in situ hybridization study, To analyze the mechanism of ADF/TRX induction during T cell activation, the effects of immunosuppressants including FK506, rapamycin (Rap) and cyclosporin A (CsA) on ADF/TRX expression were investigated by immunoblot analysis, ADF/TRX induction in PBMC by PHA, Con A or OKT3 mAb was almost completely suppressed by FK506, Whereas CsA also inhibited ADF/TRX expression in OKT3 mAb-stimulated PBMC, nap failed to affect it in spite of exhibiting growth inhibition, In addition, exogenous IL-2 could not increase ADF/TRX production in FK506-treated PBMC or in PHA blasts, These results indicate that ADF/TRX induction in T cell activation depends on calcineurin-dependent events in the early phase and that IL-2 production is not directly involved in ADF/TRX induction, Furthermore, when recombinant ADF (rADF) was added to a culture of PBMC 1 h before the addition of PHA and FK506, the action of FK506 was partially reversed as determined by [H-3]thymidine incorporation and viable cell counts, These results suggest that ADF/TRX produced and released from PBMC may be a crucial event in lymphocyte activation, and that FK506 and CsA may exert the immune suppression partly through inhibiting the induction of the endogenous reducing factor ADF/TRX.