Related Experiment Videos
The interleukin-4 receptor activates STAT5 by a mechanism that relies upon common gamma-chain
A Lischke1, R Moriggl, S Brändlein
1Theodor-Boveri-Institut für Biowissenschaften (Biozentrum), Physiologische Chemie II, Am Hubland, D-97074 Würzburg, Germany.
Abstract:
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 (gammac), is also connected to a signaling pathway that involves STAT5. 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, STAT5 became activated in an IL-4-dependent fashion as assayed by IL-4-induced STAT5 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 up-regulation of STAT5 target genes. IL-4 receptor-mediated STAT5 activation is dependent on the presence of gammac and JAK3 within the receptor complex. In COS-7 cells, the JAK/STAT pathway leading from the IL-4 receptor to STAT5-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 STAT5 activation can be triggered exclusively by IL-4R heterodimers containing gammac.
Insights
Interleukin-4 (IL-4) signaling activates STAT5, a signal transducer and activator of transcription. This pathway, dependent on the common gamma chain (gammac) and JAK3, regulates gene expression in immune cells.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- Interleukin-4 (IL-4) is a key cytokine in immune responses.
- IL-4 signaling typically involves Janus kinases (JAKs) and signal transducers and activators of transcription (STATs), primarily STAT6.
- The IL-4 receptor complex includes the common gamma chain (gammac), shared by other cytokine receptors.
Purpose of the Study:
- To investigate novel signaling pathways activated by IL-4 receptor stimulation.
- To determine the role of STAT5 in IL-4 signaling.
- To elucidate the molecular components required for IL-4-mediated STAT5 activation.
Main Methods:
- Utilized murine pro-B cell line Ba/F3 and preactivated human T cells.
- Assayed STAT5 activation via tyrosine phosphorylation, DNA-binding, and nuclear translocation.
- Employed reporter gene assays in COS-7 cells to assess JAK/STAT pathway components.
- Investigated receptor dimerization effects on STAT5 activation.
Main Results:
- IL-4 receptor stimulation leads to STAT5a and STAT5b tyrosine phosphorylation and DNA-binding in Ba/F3 cells.
- STAT5 activation (nuclear translocation and DNA-binding) occurs in response to IL-4 in human T cells.
- IL-4 up-regulates STAT5 target gene transcription in human T cells.
- STAT5 activation is dependent on the common gamma chain (gammac) and JAK3.
- JAK3 is crucial for the IL-4 receptor-mediated JAK/STAT pathway to STAT5.
- STAT5 activation is triggered by IL-4 receptor heterodimers containing gammac.
Conclusions:
- IL-4 signaling activates STAT5 in addition to the known STAT6 pathway.
- The gammac chain and JAK3 are essential for IL-4-induced STAT5 activation.
- This identifies a novel IL-4 signaling axis involving STAT5, with implications for understanding immune cell regulation.