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

The immune system is an important target for the cytokine TGF-b1, whose actions on lymphocytes are largely inhibitory. TGF-b has been reported to inhibit IL-12and IL-2-induced cell proliferation and IFN-g 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-b blocks cytokineinduced Janus kinase (JAK) and STAT activation, as in the case of IL-2. In contrast, other studies with cytokines like IFN-g have not found such an inhibition. The effect of TGF-b on the IL-12-signaling pathway has not been addressed. We examined this and found that TGF-b1 did not have any effect on IL-12-induced phosphorylation of JAK2, TYK2, and STAT4 although TGF-b1 inhibited IL-2and IL-12-induced IFN-g production. Similarly, but in contrast to previous reports, we found that TGF-b1 did not inhibit IL-2-induced phosphorylation of JAK1, JAK3, and STAT5A. Furthermore, gel shift analysis showed that TGF-b1 did not prevent activated STAT4 and STAT5A from binding to DNA. Our results demonstrate that the inhibitory effects of TGF-b on IL-2and 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-b. The Journal of Immunology, 1999, 162: 2974–2981.