IL-13 is an immunoregulatory cytokine secreted predominantly by activated TH2 cells, as well as mast cells and basophils, and is a key mediator in the pathogenesis of allergic inflammation. The human IL-13 receptor (IL-13R) is a heterodimer composed of the interleukin-4 receptor a chain (IL-4Rα) and an IL-13 binding protein, IL-13Rα1.A second IL-13 binding protein, IL-13Rα2, has also been identified, which is believed to act as a "decoy" receptor. IL-13 receptors are expressed on human B cells, basophils, eosinophils, mast cells, endothelial cells, fibroblasts, monocytes, macrophages, respiratory epithelial cells, and smooth muscle cells. However, functional IL-13 receptors have not been demonstrated on human or mouse T cells.
As with other cytokine receptors, the cytoplasmic tails of IL-4 and IL-13 receptor subunits associate with tyrosine kinases of the Janus family (JAK 1–3, TYK2): IL-4Rα associates with JAK1, whereas IL-13Rα1 interacts with either JAK2 or TYK2. One critical signaling pathway activated by IL-4R leads to tyrosine phosphorylation of STAT6, a latent cytoplasmic transcription factor in the family of signal transducers and activators of transcription (STAT). STAT6 is central in gene regulation and the IL-4– and IL-13–regulated allergic responses, including TH2 differentiation, IgE production, and chemokine and mucus production at sites of allergic inflammation. STAT6 also regulates gene expression involved in cell survival, including E4 binding protein–4 (E4BP4) and growth factor–induced gene–1 (GFI-1), suggesting that the STAT6 pathway helps regulate lymphocyte growth and survival. A second mechanism of signal transduction activated by IL-4 and IL-13 leads to the insulin receptor substrate (IRS) family, which consists of four proteins (IRS-1 to IRS-4). IRS-1, -2, and -3 can interact with IL-4R, but IRS-2 is the main family member expressed in hematopoietic cells. Tyrosine-phosphorylated sites within the IRS proteins associate with cytoplasmic signaling molecules containing SH2 domains, including the p85 subunit of phosphoinositide 3-kinase (PI3K), which results in activation of the p110 catalytic subunit of PI3K. Pathways downstream of PI3K are important for growth, survival, and regulation of gene expression in response to IL-4 and IL-13. |
