IL-3 Signaling

Interleukin 3 (IL-3), also called multi-CSF, is a cytokine that regulates hematopoiesis. It is produced by T cells and mast cells, after activation with mitogens or antigens. It stimulates eosinophils and B cell differentiation while it inhibits LAK cell activity. IL-3 shares several biological activities with GM-CSF. IL-3 is capable of inducing the growth and differentiation of multi-potential haematopoetic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid and erythroid cells. IL-3R is essential for signal transduction in cell proliferation and differentiation induced by these cytokines, and plays a major role in recruiting intracellular signaling molecules such as JAK2 tyrosine kinase and STAT5.The α and βc chains of the IL-3 receptor are not associated in the absence of ligand. The presence of ligand induces α and βc chain association to form a heterodimeric complex. Receptor activation is followed by activation of receptor associated JAK2 kinase and tyrosine and serine phosphorylation of the βc chain cytoplasmic tail. Activation of JAK2 leads to phosphorylation of the IL-3R βc chain on multiple tyrosine residues which in turn serve as docking sites for other signal transducing proteins, the most important of which are STATs. IL-3 activation of hematopoetic cells appears to lead to the activation of multiple STATs, which includes STAT1, STAT3, STAT5 and STAT6. In addition, stimulation with IL-3 leads to morphological changes of cells through tyrosine phosphorylation of βc and its associated protein pp90. In unstimulated cells, ectopically expressed RON tyrosine kinase localizes with the IL-3 receptor βc.Src family kinases mediate the phosphorylation of STAT3 mediated by IL-3/receptor interactions and play a critical role in signal transduction pathways associated with myeloid cell proliferation. One or both isoforms of STAT5 interact directly with JAK2, which in turn mediates their phosphorylation, STAT3 activation require its interaction with c-Src, which in turn mediates its phosphorylation. In addition to the activation of STATs, IL-3 activates multiple signal transduction pathways, which includes the Ras and PI3K (Phosphatidylinositol-3 Kinase) pathways. Upon IL-3 stimulation, the adapter molecule SHC transforming protein is rapidly phosphorylated and associates with the phosphorylated βc subunit of IL-3. IL-3 stimulation also results in tyrosine phosphorylation of the inositol phosphatase SHIP, which forms a complex with SHC, GRB2 and SOS. This is followed by the activation of Ras and c-Raf, which results in downstream activation of ERK1 and ERK2. Activation of the cascades culminates in the increased expression of transcription factors c-Jun and c-Fos. In addition to activation of ERKs, IL-3 also activates p38 and JNK. IL-3 induces a rapid activation of the lipid kinase PI3K. Downstream proteins recruited by the PI3K pathways upon IL-3 stimulation includes the Akt protein. Another downstream protein activated in response to IL-3 stimulation is p70S6k, which also mediates its effect via interaction with βc chain. Another protein that feeds into the PI3K-PKB/AKT pathway is the Cbl protein, which also docks onto the adaptor protein GRB2 and SHC. The BCL2 family mediates the cell survival function of IL-3. BCL2 and BCLXL are rapidly induced by IL-3, which depends upon JAK2 activation. IL-3 also regulates the glycolytic pathway. In Baf-3 cells IL-3 starvation leads to a decrease in glucose uptake and in lactate production. It is found that the eosinophils activated by IL-3 may contribute to T cell activation in allergic and parasitic diseases by presenting superantigens and peptides to T-Cells.