MODULATION OF TRANSFORMING GROWTH-FACTOR-BETA-1 EFFECTS BY CYTOKINES

The purpose of the present study was to determine the effects of human recombinant transforming growth factor-beta1 (TGF-beta1) on the proli feration of normal cell and cancer cell lines and to evaluate the mech anism of TGF-beta-induced immunosuppression. Murine H238 fibrosarcoma and human UC-11 glioblastoma cells showed no proliferative change in t he presence of TGF-beta, whereas the growth of human LS174T colon aden ocarcinoma cells was significantly enhanced at the lower concentration s of TGF-beta. In contrast, Mono/Mac-6, a human monocyte cell line, hu man peripheral blood mononuclear (PBMN) cells, and BALB/c mouse spleen cells were significantly suppressed by 2.5 to 250 ng/ml of TGF-beta. In order to investigate the mode of action, TGF-beta and other cytokin es were added 0, 1, and 2 days after initiation of the culture. Mono/M ac-6 cells showed that 2 days are needed for TGF-beta-induced suppress ion. Simultaneous addition of TGF-beta and tumor necrosis-alpha (TNF-a lpha; 600 units/ml) to Mono/Mac-6 cells resulted in nearly complete su pplression by day 3. IL-2, and to a lesser extent IL-4, was able to co unteract the suppressive effects of TGF-beta on mitogen-stimulated spl een cells. However, our results in IL-2 is not as effective in restori ng responsiveness once T cell activation is well underway. IL-1 and in terferon-gamma had no effects on TGF-beta-mediated immunosuppression. Since TGF-beta depressed normal cell growth and since IL-2 could effec tively counteract the suppression, we assayed for IL-2 production. Whe n normal spleen cells were treated with 2.5 ng of TGF-beta/ml, a 3.4-f old decrease in IL-2 production was observed. This is a potential mech anism for TGF-beta-mediated immunosuppression.