IL-13 receptors and signaling pathways: an evolving web

IL-13 is an immunoregulatory cytokine secreted predominantly by activated T(H)2 cells. Over the past several years, it has become evident that IL-13 is a key mediator in the pathogenesis of allergic inflammation. IL-13 shares many functional properties with IL-4, stemming from the fact that they share a common receptor subunit, the alpha subunit of the IL-4 receptor (IL-4Ralpha). Characterization of IL-13-deficient mice, IL-4-deficient mice, and IL-4 receptor alpha-deficient (IL-4Ralpha(-/-)) mice have demonstrated nonredundant roles for IL-13. IL-13 mediates its effects by interacting with a complex receptor system comprised of IL-4Ralpha and two IL-13 binding proteins, IL-13Ralpha1 and IL-13Ralpha2. 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. Thus unlike IL-4, IL-13 does not appear to be important in the initial differentiation of CD4 T cells into T(H)2-type cells but rather appears to be important in the effector phase of allergic inflammation. This is further supported by many in vivo observations, including that administration of IL-13 resulted in allergic inflammation, tissue-specific overexpression of IL-13 in the lungs of transgenic mice resulted in airway inflammation and mucus hypersecretion, IL-13 blockade abolished allergic inflammation independently of IL-4, and IL-13 appears to be more important than IL-4 in mucus hypersecretion. Given the importance of IL-13 as an effector molecule, regulation at the level of its receptors might be an important mechanism of modulating IL-13 responses and thus propagation of the allergic response. Accordingly, IL-13 is an attractive, novel therapeutic target for pharmacologic intervention in allergic disorders. This review will summarize the current understanding of the IL-13 receptors and signaling pathways, emphasizing recent observations.