PROTEIN-TYROSINE KINASE-DEPENDENT ACTIVATION OF STAT TRANSCRIPTION FACTORS IN INTERLEUKIN-2-STIMULATED OR INTERLEUKIN-4-STIMULATED T-LYMPHOCYTES

The proliferation of activated T lymphocytes is critically dependent o n the binding of the T-cell growth factors, interleukin (IL)-2 and IL- 4, to distinct but evolutionarily related cell surface receptors. Prev ious results suggest that the IL-2 receptor (IL-2R) and IL-4R are coup led to both overlapping and distinct intracellular signaling pathways in T lymphocytes. In this study, we demonstrate that activation of Jan us tyrosine kinases (JAKs) and STAT transcription factors is rapidly i nduced by exposure of factor-dependent murine T cell lines to IL-2 or IL-4, Both IL-2 and IL-4 stimulated the rapid activation of JAK1 and J AK3, whereas JAK2 activity was unaffected by either cytokine. These re sponses were accompanied by the appearance in cell nuclei of 3 DNA bin ding activities that recognized a high-affinity binding site for STAT factors, In transient transfection assays, this STAT factor target seq uence conferred IL-2 and IL-4 inducibility on a synthetic luciferase r eporter gene, Antibody supershifting experiments indicated that IL-2 i nduces the formation of STAT dimers containing STATE and STAT1 alpha. Although IL-4 also activated STAT1 alpha, the major IL4-induced STAT f actor is not STAT3 and remains undefined, Pretreatment of the T-cells with the protein-tyrosine kinase inhibitor herbimycin A blocked both t he nuclear translocation of STAT factors and STAT-dependent reporter g ene transcription, Immunoblot analyses confirmed that cytoplasmic STAT 3 was heavily phosphorylated on tyrosine in IL-a-stimulated cells, and that phosphorylated STAT3 appeared in the nuclei of these cells, Thes e results indicate that identical JAKs and partially overlapping sets of STATs are activated by IL-2 and IL-4 in T lymphocytes.