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.
Hershey
Gurjit K Khurana
GK
Division of Allergy, and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, USA.
D000818:Animals; D016207:Cytokines / Q000502:physiology; D006801:Humans; D018793:Interleukin-13 / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D053661:Interleukin-13 Receptor alpha1 Subunit; D053613:Janus Kinase 1; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D018123:Receptors, Interleukin / Q000502:physiology*; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4 / Q000502:physiology; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology; D018909:src Homology Domains
D016207:Cytokines; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1