The interleukin-4 receptor activates STAT5 by a mechanism that relies upon common γ-chain

Interleukin (IL)-4 signaling proceeds via cytoplasmic activation of the Janus kinases JAK1 and JAK3 and the signal transducer and activator of transcription STAT6. We show that the IL-4 receptor, like other cytokine receptor systems utilizing the common receptor gamma-chain (gamma c), is also connected to a signaling pathway that involves STATE. Both STAT5a and STAT5b become tyrosine-phosphorylated and acquire specific 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-induced 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 target genes. IL-4 receptor-mediated STATE activation is dependent on the 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-dependent regulation of a reporter gene relied largely on coexpression of JAK3. In Ba/F3 cells, studies on signal transduction evoked by directed specific receptor homo- or heterodimerization revealed that STATE activation can be triggered exclusively by IL-4R heterodimers containing gamma c.