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Lymphocyte Cell Biology Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal Diseases, National Institutes of Health, Bethesda, MD 20892
The immune system is an important target for the cytokine TGF-ß1,
whose actions on lymphocytes are largely inhibitory. TGF-ß has been
reported to inhibit IL-12- and IL-2-induced cell proliferation and
IFN-
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-ß blocks cytokine-induced Janus kinase (JAK) and
STAT activation, as in the case of IL-2. In contrast, other studies
with cytokines like IFN- have not found such an inhibition. The
effect of TGF-ß on the IL-12-signaling pathway has not been
addressed. We examined this and found that TGF-ß1 did not have any
effect on IL-12-induced phosphorylation of JAK2, TYK2, and STAT4
although TGF-ß1 inhibited IL-2- and IL-12-induced IFN- production.
Similarly, but in contrast to previous reports, we found that TGF-ß1
did not inhibit IL-2-induced phosphorylation of JAK1, JAK3, and STAT5A.
Furthermore, gel shift analysis showed that TGF-ß1 did not prevent
activated STAT4 and STAT5A from binding to DNA. Our results demonstrate
that the inhibitory effects of TGF-ß 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-ß.
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