TRANSFORMING GROWTH-FACTOR BETA(1) INHIBITS INTERLEUKIN-1-INDUCED BUTENHANCES IONOMYCIN-INDUCED INTERFERON-GAMMA PRODUCTION IN A T-CELL LYMPHOMA - COMPARISON WITH THE EFFECTS OF RAPAMYCIN

Transforming growth factor beta 1 (TGF-beta 1) is a multifunctional cy tokine whose potent immunomodulatory activity is well documented. To e xplore the mechanisms of this activity we examined the effect of TGF-b eta 1 on the production of IFN-gamma measured at the mRNA and protein levels in the YAC-1 T cell lymphoma. In previous studies, this model p roved useful to characterize the mode of action of the immunosuppressa nt rapamycin (RAP). Here, we found that when induced by IL-1 or IL-1 PMA, the production of IFN-gamma is suppressed by both TGF-beta 1 (ED (50) = 1.9 pM) and RAP (ED(50) = 0.2 nM). In contrast, when induced by the calcium ionophore ionomycin, in the absence or in the presence of PMA, this production is enhanced up to 10-fold by TGF-beta 1 (ED(50) = 1.8 pM) and 1.5-3-fold by RAP. Therefore, in YAC-1 cells, TGF-beta 1 exerts opposite effects on IFN-gamma production depending on the mode of activation, and these effects parallel those of RAP. To further an alyze the mode of action of TGF-beta 1 in this system, we used okadaic acid (OA), an inhibitor of serine/threonine protein phosphatases. Tre atment with OA rendered the expression of IFN-gamma mRNA induced by IL -1 insensitive to TGF-beta 1 or RAP, indicating that activation of a p hosphatase may play a role in the suppressive effect of bath agents. H owever, OA did not prevent the augmentation of ionomycin-mediated indu ction of IFN-gamma mRNA by either TGF-beta 1 or RAP. Hence, the up-reg ulation of IFN-gamma production by TGF-beta 1 and RAP may involve a di fferent biochemical mechanism than that mediating their suppressive ac tion. These observations also favor the hypothesis that the two agents act on the same regulatory pathways. This was further supported by th e finding that TGF-beta 1 and RAP modulate IFN-gamma production in an additive rather than synergistic fashion. However, their effects could be dissociated in mutants of YAC-1 cells selected for resistance to t he inhibition of IL-1-mediated IFN-gamma induction by RAP. Moreover, t he IFN-gamma modulatory action of RAP in YAC-1 cells was accompanied b y an antiproliferative effect, whereas TGF-beta 1 failed to alter the growth of these cells. Therefore, the immunomodulatory action of TGF-b eta 1 may result from the dis disruption of biochemical processes rela ted to, although distinct from, those affected by RAP. (C) 1994 Wiley- Liss, Inc.