TGF-beta 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-beta 1, whose actions on lymphocytes are largely inhibitory. TGF-beta has been reported to inhibit IL-12- and IL-2-induced cell proliferation and IFN-gamma product ion 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-beta blocks cytokine-induced Jams kinase (JAK) and STAT activation, as in the ca se of IL-2, In contrast, other studies with cytokines like IFN-gamma have n ot found such an inhibition. The effect of TGF-beta on the IL-12-signaling pathway has not been addressed. We examined this and found that TGF-beta 1 did not have any effect on IL-12-induced phosphorylation of JAK2, TYK2, and STAT4 although TGF-beta 1 inhibited IL-2- and IL-12-induced IFN-gamma prod uction. Similarly, but in contrast to previous reports, we found that TGF-b eta 1 did not inhibit IL-2-induced phosphorylation of JAK1, JAK3, and STAT5 A, Furthermore, gel shift analysis showed that TGF-beta 1 did not prevent: activated STAT4 and STAT5A from binding to DNA. Our results demonstrate tha t the inhibitory effects of TGF-beta on IL-2- and IL-12-induced biological activities are not attributable to inhibition of activation of JAKs and STA Ts, Rather, our data suggest the existence of alternative mechanisms of inh ibition by TGF-beta.