TGF-β Does Not Inhibit IL-12- and IL-2-Induced Activation of Janus Kinases and STATs

Abstract

The immune system is an important target for the cytokine TGF-β1, whose actions on lymphocytes are largely inhibitory. TGF-β has been reported to inhibit IL-12- and IL-2-induced cell proliferation and IFN-γ production by T cells and NK cells; however, the mechanisms of inhibition have not been clearly defined. It has been suggested by some studies that TGF-β blocks cytokine-induced Janus kinase (JAK) and STAT activation, as in the case of IL-2. In contrast, other studies with cytokines like IFN-γ have not found such an inhibition. The effect of TGF-β on the IL-12-signaling pathway has not been addressed. We examined this and found that TGF-β1 did not have any effect on IL-12-induced phosphorylation of JAK2, TYK2, and STAT4 although TGF-β1 inhibited IL-2- and IL-12-induced IFN-γ production. Similarly, but in contrast to previous reports, we found that TGF-β1 did not inhibit IL-2-induced phosphorylation of JAK1, JAK3, and STAT5A. Furthermore, gel shift analysis showed that TGF-β1 did not prevent activated STAT4 and STAT5A from binding to DNA. Our results demonstrate that the inhibitory effects of TGF-β on IL-2- and IL-12-induced biological activities are not attributable to inhibition of activation of JAKs and STATs. Rather, our data suggest the existence of alternative mechanisms of inhibition by TGF-β.