IL-13 receptors and signaling pathways: An evolving web☆☆☆★

Abstract 

Continuing Medical Education examination

IL-13 is an immunoregulatory cytokine secreted predominantly by activated T_H2 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 α subunit of the IL-4 receptor (IL-4Rα). Characterization of IL-13–deficient mice, IL-4–deficient mice, and IL-4 receptor α–deficient (IL-4Rα^−/−) mice have demonstrated nonredundant roles for IL-13. IL-13 mediates its effects by interacting with a complex receptor system comprised of IL-4Rα and two IL-13 binding proteins, IL-13Rα1 and IL-13Rα2. 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_H2-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. (J Allergy Clin Immunol 2003;111:677-90.)

Keywords:  IL-13, cytokine, receptor, Janus kinase, signal transducer and activator of transcription, suppressor of cytokine signaling, protein inhibitor of activated signal transducer and activator of transcription, review

Abbreviations:  CIS: , Cytokine-inducible SH2-containing protein, γc: , Common γ chain, IRS: , Insulin receptor substrate, ITIM: , Immunotyrosine-based inhibitory motif, JAK: , Janus kinase, NES: , Nuclear export signal, PI3: , Phosphoinositol 3, PIAS: , Protein inhibitor of activated signal transducer and activator of transcription, SHP-1: , SH2 domain-containing tyrosine phosphatase 1, SOCS: , Suppressor of cytokine signaling, STAT: , Signal transducer and activator of transcription