Modulation of Transforming Growth Factor-β1 Effects by Cytokines

Abstract

The purpose of the present study was to determine the effects of human recombinant transforming growth factor-β1 (TGF-β1) on the proliferation of normal cell and cancer cell lines and to evaluate the mechanism of TGF-β-induced immunosuppression. Murine H238 fibrosarcoma and human UC-11 glioblastoma cells showed no proliferative change in the presence of TGF-β, whereas the growth of human LS174T colon adenocarcinoma cells was significantly enhanced at the lower concentrations of TGF-β. In contrast, Mono/Mac-6, a human monocyte cell line, human peripheral blood mononuclear (PBMN) cells, and BALB/c mouse spleen cells were significantly suppressed by 2.5 to 250 ng/ml of TGF-β. In order to investigate the mode of action, TGF-β and other cytokines were added 0,1, and 2 days after initiation of the culture. Mono/Mac-6 cells showed that 2 days are needed for TGF-β-induced suppression. Simultaneous addition of TGF-β and tumor necrosis-α (TNF-α; 600 units/ml) to Mono/Mac-6 cells resulted in nearly complete suppression by day 3. IL-2, and to a lesser extent IL-4, was able to counteract the suppressive effects of TGF-β on mitogen-stimulated spleen cells. However, our results indicate that IL-2 is not as effective in restoring responsiveness once T cell activation is well underway. IL-1 and interferon-γ had no effects on TGF-β-mediated immunosuppression. Since TGF-β depressed normal cell growth and since IL-2 could effectively counteract the suppression, we assayed for IL-2 production. When normal spleen cells were treated with 2.5 ng of TGF-β/ml, a 3.4-fold decrease in IL-2 production was observed. This is a potential mechanism for TGF-β-mediated immunosuppression.