Abstract
Interleukin (IL)-13 is an immunoregulatory cytokine secreted predominantly by activated T-helper type 2 (Th2) cells, and it has been identified as crucial in developing allergic inflammatory responses. Its diverse functions are mediated by a complex receptor system including IL-4 receptor α (IL-4Rα; CD124) and two other cognate cell surface proteins, IL-13Rα1 (CD213a1) and IL-13Rα2 (CD213a2). IL-13Rα1 forms a heterodimer with IL-4Rα that is a signaling IL-13 receptor. In contrast, IL-13Rα2 has been thought to be a decoy receptor due to its short cytoplasmic tail. IL-13Rα2 exists on the cell membrane, intracellularly, and in soluble form. Recent reports revealed that membrane IL-13Rα2 may have some signaling capabilities, and soluble IL-13Rα2 is a critical endogenous modulator for IL-13 responses. The receptor has more complicated functions than a simple decoy receptor. In this review, we describe the isoforms of IL-13Rα2 and discuss newly revealed functions of IL-13Rα2.
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References and Recommended Reading
Wills-Karp M: Interleukin-13 in asthma pathogenesis. Curr Allergy Asthma Rep 2004, 4:123–131.
Hershey GK: IL-13 receptors and signaling pathways: an evolving web. J Allergy Clin Immunol 2003, 111:677–690.
Miloux B, Laurent P, Bonnin O, et al.: Cloning of the human IL-13R alpha1 chain and reconstitution with the IL4R alpha of a functional IL-4/IL-13 receptor complex. FEBS Lett 1997, 401:163–166.
Donaldson DD, Whitters MJ, Fitz LJ, et al.: The murine IL-13 receptor alpha 2: molecular cloning, characterization, and comparison with murine IL-13 receptor alpha 1. J Immunol 1998, 161:2317–2324.
Zhang JG, Hilton DJ, Willson TA, et al.: Identification, purification, and characterization of a soluble interleukin (IL)-13-binding protein. Evidence that it is distinct from the cloned Il-13 receptor and Il-4 receptor alpha-chains. J Biol Chem 1997, 272:9474–9480.
Daines MO, Tabata Y, Walker BA, et al.: Level of expression of IL-13R alpha 2 impacts receptor distribution and IL-13 signaling. J Immunol 2006, 176:7495–7501.
Andrews AL, Holloway JW, Puddicombe SM, et al.: Kinetic analysis of the interleukin-13 receptor complex. J Biol Chem 2002, 277:46073–46078.
Wood N, Whitters MJ, Jacobson BA, et al.: Enhanced interleukin (IL)-13 responses in mice lacking IL-13 receptor alpha 2. J Exp Med 2003, 197:703–709.
Chiaramonte MG, Mentink-Kane M, Jacobson BA, et al.: Regulation and function of the interleukin 13 receptor alpha 2 during a T helper cell type 2-dominant immune response. J Exp Med 2003, 197:687–701.
Fichtner-Feigl S, Strober W, Kawakami K, et al.: IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat Med 2006, 12:99–106.
Tabata Y, Chen W, Warrier MR, et al.: Allergy-driven alternative splicing of IL-13 receptor alpha2 yields distinct membrane and soluble forms. J Immunol 2006, 177:7905–7912.
Leonard WJ, Lin JX: Cytokine receptor signaling pathways. J Allergy Clin Immunol 2000, 105:877–888.
Arima K, Sato K, Tanaka G, et al.: Characterization of the interaction between interleukin-13 and interleukin-13 receptors. J Biol Chem 2005, 280:24915–24922.
Guo J, Apiou F, Mellerin MP, et al.: Chromosome mapping and expression of the human interleukin-13 receptor. Genomics 1997, 42:141–145.
Hilton DJ, Zhang JG, Metcalf D, et al.: Cloning and characterization of a binding subunit of the interleukin 13 receptor that is also a component of the interleukin 4 receptor. Proc Natl Acad Sci U S A 1996, 93:497–501.
Aman MJ, Tayebi N, Obiri NI, et al.: cDNA cloning and characterization of the human interleukin 13 receptor alpha chain. J Biol Chem 1996, 271:29265–29270.
Caput D, Laurent P, Kaghad M, et al.: Cloning and characterization of a specific interleukin (IL)-13 binding protein structurally related to the IL-5 receptor alpha chain. J Biol Chem 1996, 271:16921–16926.
He YW, Malek TR: The IL-2 receptor gamma c chain does not function as a subunit shared by the IL-4 and IL-13 receptors. Implication for the structure of the IL-4 receptor. J Immunol 1995, 155:9–12.
Andrews R, Rosa L, Daines M, et al.: Reconstitution of a functional human type II IL-4/IL-13 receptor in mouse B cells: demonstration of species specificity. J Immunol 2001, 166:1716–1722.
Gauchat JF, Schlagenhauf E, Feng NP, et al.: A novel 4-kb interleukin-13 receptor alpha mRNA expressed in human B, T, and endothelial cells encoding an alternate type-II interleukin-4/interleukin-13 receptor. Eur J Immunol 1997, 27:971–978.
Graber P, Gretener D, Herren S, et al.: The distribution of IL-13 receptor alpha1 expression on B cells, T cells and monocytes and its regulation by IL-13 and IL-4. Eur J Immunol 1998, 28:4286–4298.
Akaiwa M, Yu B, Umeshita-Suyama R, et al.: Localization of human interleukin 13 receptor in non-haematopoietic cells. Cytokine 2001, 13:75–84.
Osawa M, Miyoshi S, Copeland NG, et al.: Characterization of the mouse interleukin-13 receptor alpha1 gene. Immunogenetics 2000, 51:974–981.
Miyoshi M, Horiuchi H, Fukushima Y, et al.: Cloning of the chicken interleukin-13 receptor alpha2 gene and production of a specific monoclonal antibody. Dev Comp Immunol 2007, 31:394–406.
Matsushita M, Yamamoto T, Nishioka K: Upregulation of interleukin-13 and its receptor in a murine model of bleomycin-induced scleroderma. Int Arch Allergy Immunol 2004, 135:348–356.
Morimoto M, Morimoto M, Zhao A, et al.: Functional importance of regional differences in localized gene expression of receptors for IL-13 in murine gut. J Immunol 2006, 176:491–495.
Murata T, Husain SR, Mohri H, et al.: Two different IL-13 receptor chains are expressed in normal human skin fibroblasts, and IL-4 and IL-13 mediate signal transduction through a common pathway. Int Immunol 1998, 10:1103–1110.
Kioi M, Seetharam S, Puri RK: N-linked glycosylation of IL-13R alpha2 is essential for optimal IL-13 inhibitory activity. FASEB J 2006, 20:2378–2380.
Chen W, Khurana Hershey GK: Signal transducer and activator of transcription signals in allergic disease. J Allergy Clin Immunol 2007, 119:529–541.
Andrews RP, Ericksen MB, Cunningham CM, et al.: Analysis of the life cycle of stat6. Continuous cycling of STAT6 is required for IL-4 signaling. J Biol Chem 2002, 277:36563–36569.
Orchansky PL, Kwan R, Lee F, et al.: Characterization of the cytoplasmic domain of interleukin-13 receptor-alpha. J Biol Chem 1999, 274:20818–20825.
Wery-Zennaro S, Letourneur M, David M, et al.: Binding of IL-4 to the IL-13Ralpha(1)/IL-4Ralpha receptor complex leads to STAT3 phosphorylation but not to its nuclear translocation. FEBS Lett 1999, 464:91–96.
Umeshita-Suyama R, Sugimoto R, Akaiwa M, et al.: Characterization of IL-4 and IL-13 signals dependent on the human IL-13 receptor alpha chain 1: redundancy of requirement of tyrosine residue for STAT3 activation. Int Immunol 2000, 12:1499–1509.
Rahaman SO, Sharma P, Harbor PC, et al.: IL-13R(alpha)2, a decoy receptor for IL-13 acts as an inhibitor of IL-4-dependent signal transduction in glioblastoma cells. Cancer Res 2002, 62:1103–1109.
Andrews AL, Nasir T, Bucchieri F, et al.: IL-13 receptor alpha 2: a regulator of IL-13 and IL-4 signal transduction in primary human fibroblasts. J Allergy Clin Immunol 2006, 118:858–865.
Rahaman SO, Vogelbaum MA, Haque SJ: Aberrant Stat3 signaling by interleukin-4 in malignant glioma cells: involvement of IL-13Ralpha2. Cancer Res 2005, 65:2956–2963.
Yasunaga S, Yuyama N, Arima K, et al.: The negative-feedback regulation of the IL-13 signal by the IL-13 receptor alpha2 chain in bronchial epithelial cells. Cytokine 2003, 24:293–303.
Heller NM, Matsukura S, Georas SN, et al.: Interferongamma inhibits STAT6 signal transduction and gene expression in human airway epithelial cells. Am J Respir Cell Mol Biol 2004, 31:573–582.
Jakubzick C, Choi ES, Joshi BH, et al.: Therapeutic attenuation of pulmonary fibrosis via targeting of IL-4-and IL-13-responsive cells. J Immunol 2003, 171:2684–2693.
Kawashima R, Kawamura YI, Kato R, et al.: IL-13 receptor alpha2 promotes epithelial cell regeneration from radiation-induced small intestinal injury in mice. Gastroenterology 2006, 131:130–141.
David M, Ford D, Bertoglio J, et al.: Induction of the IL-13 receptor alpha2-chain by IL-4 and IL-13 in human keratinocytes: involvement of STAT6, ERK and p38 MAPK pathways. Oncogene 2001, 20:6660–6668.
Yoshikawa M, Nakajima T, Tsukidate T, et al.: TNF-alpha and IL-4 regulate expression of IL-13 receptor alpha2 on human fibroblasts. Biochem Biophys Res Commun 2003, 312:1248–1255.
Zhao Y, He D, Zhao J, et al.: Lysophosphatidic acid induces IL-13 receptor alpha 2 expression and inhibits IL-13 signaling in primary human bronchial epithelial cells. J Biol Chem 2007, 282:10172–10179.
David MD, Bertoglio J, Pierre J: Functional characterization of IL-13 receptor alpha2 gene promoter: a critical role of the transcription factor STAT6 for regulated expression. Oncogene 2003, 22:3386–3394.
Wu AH, Low WC: Molecular cloning and identification of the human interleukin 13 alpha 2 receptor (IL-13Ra2) promoter. Neuro-oncol 2003, 5:179–187.
Daines MO, Hershey GK: A novel mechanism by which interferon-gamma can regulate interleukin (IL)-13 responses. Evidence for intracellular stores of IL-13 receptor alpha-2 and their rapid mobilization by interferon-gamma. J Biol Chem 2002, 277:10387–10393.
Kawakami K, Takeshita F, Puri RK: Identification of distinct roles for a dileucine and a tyrosine internalization motif in the interleukin (IL)-13 binding component IL-13 receptor alpha 2 chain. J Biol Chem 2001, 276:25114–25120.
Levine SJ: Mechanisms of soluble cytokine receptor generation. J Immunol 2004, 173:5343–5348.
Leigh R, Ellis R, Wattie J, et al.: Is interleukin-13 critical in maintaining airway hyperresponsiveness in allergenchallenged mice? Am J Respir Crit Care Med 2004, 170:851–856.
Mentink-Kane MM, Cheever AW, Thompson RW, et al.: IL-13 receptor alpha 2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. Proc Natl Acad Sci U S A 2004, 101:586–590.
Daines MO, Chen W, Tabata Y, et al.: Allergen-dependent solubilization of IL-13 receptor alpha2 reveals a novel mechanism to regulate allergy. J Allergy Clin Immunol 2007, 119:375–383.
Plante S, Semlali A, Joubert P, et al.: Mast cells regulate procollagen I (alpha 1) production by bronchial fibroblasts derived from subjects with asthma through IL-4/IL-4 delta 2 ratio. J Allergy Clin Immunol 2006, 117:1321–1327.
Granel B, Allanore Y, Chevillard C, et al.: IL13RA2 gene polymorphisms are associated with systemic sclerosis. J Rheumatol 2006, 33:2015–2019.
Kawakami K, Terabe M, Kawakami M, et al.: Characterization of a novel human tumor antigen interleukin-13 receptor alpha2 chain. Cancer Res 2006, 66:4434–4442.
Minn AJ, Gupta GP, Siegel PM, et al.: Genes that mediate breast cancer metastasis to lung. Nature 2005, 436:518–524.
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Tabata, Y., Khurana Hershey, G.K. IL-13 receptor isoforms: Breaking through the complexity. Curr Allergy Asthma Rep 7, 338–345 (2007). https://doi.org/10.1007/s11882-007-0051-x
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DOI: https://doi.org/10.1007/s11882-007-0051-x