Inhibitory cytokine circuits involving transforming growth factor-β, interferon-γ, and interleukin-2 in human monocyte activation

Abstract

We have previously reported that transforming growth factor-β1 (TGF- β1) inhibits interleukin-6 (IL-6) induction by IL-2 and IL-1 in fresh human monocytes. We investigated the effects of TGF-β1 on the expression of tumoricidal activity induced by IL-2 or interferon-γ (IFN-γ) in human monocytes. We showed that TGF-β1 specifically inhibited, in a dose- dependent manner, IL-2-induced but not IFN-γ-induced monocyte tumoricidal activity. The inhibitory effects of TGF-β1 on IL-2-activated monocytes were not caused by down-modulation of the IL-2 receptor β (IL-2Rβ) because the treatment of monocytes with IL-2 and TGF-β1 increased IL-2Rβ mRNA expression. However, we found that TGF-β1 down-modulated IL-2-induced IL- 2Rγ mRNA, which may be responsible for the TGF-β1 inhibition of monocyte activation by IL-2. The resistance of the IFN-γ-induced activation to the inhibitory effects of TGF-β1 could be caused by the ability of IFN-γ to decrease TGF-β1 receptor expression, as shown by cross-linking experiments. Overall, these results showed that TGF-β1 is a powerful inhibitor of IL-2- but not of IFN-γ-induced activation of monocytes to a cytotoxic stage. This differential effect may be attributed to modulation of cytokine receptor expression.