THE INTERLEUKIN-4 RECEPTOR ACTIVATES STAT5 BY A MECHANISM THAT RELIESUPON COMMON GAMMA-CHAIN

Interleukin (IL)-4 signaling proceeds via cytoplasmic activation of th e Janus kinases JAK1 and JAK3 and the signal transducer and activator of transcription STAT6. We show that the IL-4 receptor, like other cyt okine receptor systems utilizing the common receptor gamma-chain (gamm a c), is also connected to a signaling pathway that involves STATE. Bo th STAT5a and STAT5b become tyrosine-phosphorylated and acquire specif ic DNA-binding properties in response to IL-4 receptor stimulation in the murine pro-B cell line Ba/F3. In preactivated human T cells, STATE became activated in an IL-4-dependent fashion as assayed by IL-Li-ind uced STATE translocation from the cytoplasm to the cell nucleus and by binding to cognate DNA. Moreover, stimulation of preactivated human T cells by IL-4 led to specific transcriptional upregulation of STATE t arget genes. IL-4 receptor-mediated STATE activation is dependent on t he presence of gamma c and JAK3 within the receptor complex. In COS-7 cells, the JAK/STAT pathway leading from the IL-4 receptor to STATE-de pendent regulation of a reporter gene relied largely on coexpression o f JAK3. In Ba/F3 cells, studies on signal transduction evoked by direc ted specific receptor homo- or heterodimerization revealed that STATE activation can be triggered exclusively by IL-4R heterodimers containi ng gamma c.