The Journal of Allergy and Clinical Immunology
Volume 111, Issue 4 , Pages 677-690, April 2003

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

Division of Allergy, and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati. Cincinnati, Ohio

Received 5 November 2002; received in revised form 6 December 2002; accepted 18 December 2002.

Article Outline

Abstract 

Continuing Medical Education examination

IL-13 is an immunoregulatory cytokine secreted predominantly by activated TH2 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 TH2-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

 

IL-13 is a critical mediator of allergic inflammation. Although it shares many functional properties with IL-4, it has been shown to have distinct functions. Furthermore, IL-13 is more important than IL-4 in the development of airway hyperreactivity and mucus production. As such, it is an obvious target for pharmacologic intervention in the treatment of asthma. It is imperative to have a solid basic understanding of IL-13 functions, receptors, and signaling pathways to design and generate effective drugs to target the IL-13 response. Considerable research effort is taking place to understand this important cytokine, how it transmits its effects, and the mechanisms by which its signaling and responses are regulated. The purpose of this article is to provide a comprehensive review of the current understanding of IL-13 receptors and signaling pathways. First, the functions of IL-13 will be reviewed. Its receptors are widely expressed, and consequently, IL-13 has many diverse effects on different cell types. Next, the components of the IL-13 receptor complex and the signaling pathways that are activated after receptor engagement will be detailed. The mechanisms by which IL-13 signaling is regulated will be discussed. Atopy-associated genetic variants of IL-13 and its receptor subunits have been described, and these data will be reviewed.

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IL-13 

Characterization and structure 

IL-13 was first described in 1989 as P600, a protein preferentially produced by activated mouse TH2 cells.1 The cDNA for human IL-13 was cloned approximately 10 years ago by 3 groups.2, 3, 4 It has a single open-reading frame with 132 amino acids, including a 20-amino-acid signal sequence that is cleaved from the mature secreted protein. Transfection of the cDNA into COS-7 cells has demonstrated that IL-13 is secreted as a 10-kd unglycosylated species.5 IL-13 belongs to the class of type I cytokines and shares the tertiary structure defined by a 4 α-helical hydrophobic bundle core.6 Although IL-13 only shares 25% homology with IL-4 at the amino acid level, the 25-amino-acid hydrophobic structural core is completely conserved, with only some conservative hydrophobic substitutions.7 IL-4 structure has been defined by means of crystallography and nuclear magnetic resonance studies8, 9; however, the tertiary structure of IL-13 is not known. Mass spectrophotometric studies have revealed that in contrast to IL-4, IL-13 contains only 2 disulfide bridges instead of 3.10 The crystallization of IL-13 and its receptors will provide very valuable information about the structure and, consequently, important clues about the function of these key molecules.

As outlined above, IL-4 and IL-13 share many structural characteristics; however, they also have some important differences. One notable difference between the 2 cytokines is in their abilities to act across species. IL-4 is absolutely species specific, such that human IL-4 acts only on human cells, and mouse IL-4 acts only on mouse cells.11 In contrast, IL-13 is not species specific. Mouse IL-13 acts on human or mouse cells with equal potency. However, IL-13 does appear to be species selective because human IL-13 has greater activity on human cells than on mouse cells.2, 5

The gene encoding IL-13 is comprised of 4 exons and 3 introns and is located 12 kb upstream of the gene encoding IL-4 on chromosome 5q31, and both genes are in the same orientation.12 This chromosomal region, 5q31, also contains the genes encoding IL-3, IL-5, IL-9, and GM-CSF4, 12 and has been linked with asthma.13, 14, 15, 16

IL-13 functions 

IL-13 has many diverse functions on a wide variety of cell types that are relevant to the pathogenesis of allergic disorders, as shown schematically in Fig 1.

These activities highlight the potent immunoregulatory role of IL-13. In human B cells human IL-13 has similar effects as IL-4, including promoting B-cell proliferation and inducing class switching to IgG4 and IgE in combination with CD40/CD40 ligand costimulation17 and inducing expression of surface antigens, including the low-affinity IgE receptor CD23 (FcϵRII) and MHC class II.7 In monocytes and macrophages IL-13 enhances the expression of many members of the integrin family important in adhesion, including CD11b, CD11c, CD18, and CD29,18 and induces MHC class II and CD23 expression.19 In addition, IL-13 inhibits the production of pro-inflammatory mediators by monocytes and macrophages, including prostaglandins,20 reactive oxygen and nitrogen intermediates,21, 22 IL-1, IL-6, IL-8, TNF-α, and IL-12,19 through a mechanism that partially involves suppression of nuclear factor κB.23 IL-13 has been reported to have direct effects on eosinophils, including promoting eosinophil survival, activation, and recruitment.24, 25, 26 IL-13 has been reported to activate mast cells and contributes to IgE priming of mast cells given its role in promoting IgE synthesis.19

IL-13 also has important functions on nonhematopoietic cells, including endothelial cells, smooth muscle cells, fibroblasts, and epithelial cells. In endothelial cells IL-13 is a potent inducer of vascular cell adhesion molecule 1, which is important in the recruitment of eosinophils.27 IL-13 enhances proliferation and cholinergic-induced contractions of smooth muscle cells in vitro28 and induces type I collagen synthesis in human dermal fibroblasts.29 In epithelial cells IL-13 is a potent inducer of chemokine expression,30 alters mucociliary differentiation,31 decreases ciliary beat frequency of ciliated epithelial cells,31 and results in goblet cell metaplasia.32, 33, 34

The net effect of these functions is to promote inflammation associated with allergic disorders and to promote changes in the airway epithelium that contribute to the pathology of asthma, while contributing to the control of helminthic infections and suppressing inflammation associated with bacterial and most viral infections. Notably, IL-13 has been reported to have no effects on mouse B cells or human or mouse T cells.18 Thus unlike IL-4, IL-13 does not appear to be important in the initial differentiation of CD4 T cells into TH2-type cells but rather appears to be important in the effector phase of allergic inflammation. This effector role, which has been further supported by many observations in vivo, including administration of IL-13, resulted in allergic inflammation,32, 34 tissue-specific overexpression of IL-13 in the lungs of transgenic mice resulted in airway inflammation and mucus hypersecretion,33 IL-13 blockade abolished allergic inflammation independently of IL-4,32, 34 and IL-13 appears to be more important than IL-4 in mucus hypersecretion.35 The effects of IL-13 on airway hyperreactivity and mucus production are independent of IL-5 and the chemokine eotaxin.36 Further evidence that IL-13 is a critical effector molecule was recently provided by a study in which IL-13 was inducibly expressed in the lungs of mice.37 Interestingly, IL-13 was found to be a potent stimulator of matrix me-talloproteinases and cathepsin proteases in the lung, and overexpression of IL-13 in the adult lung (by feeding doxycycline to the mice) resulted in emphysematous changes and mucus metaplasia.37 Thus IL-13 is an important effector molecule both in asthma and in chronic obstructive pulmonary disease phenotypes.

There is considerable evidence that IL-13 has some unique functions in vivo independent of IL-4. Some of these are discussed above, and additional evidence has been compiled by comparing IL-4−/−, IL-13−/−, STAT6−/−, and IL-4Rα−/− mice in models of allergic inflammation28 and helminth infection.38 The IL-4−/− and IL-13−/− mice are deficient in IL-4 and IL-13, respectively, whereas the STAT6−/− and IL-4Rα−/− mice are deficient in both IL-4– and IL-13–mediated responses because STAT6 and IL-4Rα are shared components of both the IL-4 and IL-13 receptor signaling pathways. Thus differences noted between the IL-4−/− and IL-4Rα−/− mice are attributed to IL-13. For example, IL-4−/− mice display normal expulsion of Nippostrongyloides brasiliensis , but the IL-4Rα−/− mice, and the STAT6−/− mice are unable to expel N brasiliensis , suggesting that IL-13, which is the only other known cytokine that uses IL-4Rα and STAT6, is responsible for IL-4–independent protection. Differences between IL-4 and IL-13 responses might be due to differences in their receptors and signaling pathways.

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IL-13 and IL-4 receptors 

IL-13 is a type I cytokine, and it signals through type I cytokine receptors. Type I cytokine receptors are defined by several features, including 4 conserved cysteine residues, a W-S-X-W-S motif, fibronectin type II modules in the extracellular domain, and proline-rich box regions in the intracellular domain that are important for binding of Janus tyrosine kinases (JAK).6 These receptors have no intrinsic kinase activity but rather have constitutively associated JAKs, which ultimately result in recruitment of downstream signaling molecules. Type I cytokine receptors form heterodimers. There are a total of 4 receptors between IL-4 and IL-13, and these are shown schematically in Fig 2.

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  • Fig. 2. 

    Schematic representation of IL-4 and IL-13 receptors and signaling pathways. The type II IL-4 receptor is also the functional receptor for IL-13 and is comprised of IL-4Rα and IL-13Rα1. Signaling is mediated predominantly through IL-4Rα and results in activation of the JAK/STAT and IRS-1/IRS-2 pathways. IL-13Rα2 binds IL-13 with high affinity but does not signal and has been hypothesized to act as a decoy receptor. [A larger version of this illustration is available in the online Journal at (www.mosby.com/jaci ).]

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IL-4Rα 

Both IL-4 and IL-13 use the IL-4Rα chain as a component of their receptors. IL-4Rα is a 140-kd protein that binds IL-4 with high affinity (dissociation constant = 100 pmol/L). Its cDNA encodes an open reading frame of 825 amino acids, including a 25-amino-acid signal sequence.39, 40 IL-4Rα has the characteristic features of a type I cytokine receptor with 4 conserved cysteines and the W-S-X-W-S motif in the extracellular domain. It contains a single transmembrane domain and a long intracellular domain, which contains a membrane proximal Box-1 sequence that serves as a docking site for JAK1 and 5 conserved tyrosine (Y) residues at positions Y497, Y575, Y603, Y631, and Y713. IL-4Rα is constitutively expressed in relatively low numbers (a few hundred to a few thousand) on every cell type that has been tested11 and is a component of both the type I and type II IL-4 receptors. The type I IL-4 receptors result from association of IL-4Rα with the common γ chain (γc), which is also a component of the receptors for IL-2, IL-7, IL-9, and IL-15.6 The γc does not bind IL-4 or IL-13 but is important for signaling of the type I receptor. Evidence that IL-4Rα is also a component of the IL-13 receptor comes from studies using potent IL-4Rα antagonists. These antagonists blocked IL-4Rα and were found to inhibit both IL-4 and IL-13 responses.41, 42 Further support was provided by studies that demonstrated that both IL-4 and IL-13 responses were inhibited by blocking antibodies against IL-4Rα.43, 44

Type II IL-4R/IL-13R 

The central role played by the γc in the signaling of multiple cytokines is the basis for the profound immunodeficiency observed in human patients when the γc is mutated.45 Cells derived from these patients were a useful tool to study the role of the γc in signaling and demonstrated that both IL-4 and IL-13 responses were intact, even in the absence of the γc.46 This suggested the presence of an alternate receptor for IL-4 and IL-13. It is now known that this alternate receptor is a heterodimer, the type II IL-4 receptor or the IL-13 receptor, which is comprised of IL-4Rα and IL-13Rα1.

IL-13 has 2 cognate receptors, IL-13Rα1 and IL-13α2.47, 48, 49, 50, 51, 52 Both IL-13Rα1 and IL-13Rα2 are members of the hematopoietin receptor superfamily (type I cytokine receptor family) and share 37% homology at the amino acid level. Their respective genes have been mapped to the X chromosome, and in vitro expression of IL-13Rα1 and IL-13Rα2 has revealed that they both specifically bind IL-13.47, 48, 49, 50, 51, 52 The cDNA for human IL-13Rα1 encodes a 427-amino-acid sequence, including a 26-amino-acid signal sequence. IL-13Rα1 is a 65- to 70-kd glycosylated protein that binds IL-13 with low affinity (Kd = 2-10 nmol/L) by itself, but when paired with IL-4Rα, it binds IL-13 with high affinity (Kd = 400 pmol/L) and forms a functional IL-13 receptor that signals.50 This receptor complex, the type II IL-4/IL-13 receptor, also serves as an alternative receptor for IL-4. The γc is not a component of the type II IL-4/IL-13 receptor. There is some evidence that overexpression of the γc might affect IL-13 function,53 but the biologic relevance of this is unclear. Overexpression of the γc by means of transfection might upset the balance between IL-13Rα1 and the γc for IL-4Rα. This could result in an increase in IL-4Rα/γc heterodimers and a compensatory decrease in IL-13Rα1/IL-4Rα heterodimers, which would diminish IL-13 signaling. However, the γc is not a component of the IL-13 receptor complex.54

The interaction between IL-4Rα and IL-13Rα1 is completely species specific, as evidenced by the fact that human IL-13Rα1 could associate only with human and not mouse IL-4α to form a functional receptor.55 The open-reading frame of human IL-13Rα1 has 81% nucleotide and 76% amino acid identity with murine IL-13Rα1.47, 49 The epitopes on IL-13Rα1 for binding IL-4Rα must not be conserved between human patients and mice. This is surprising because the epitope on the mouse IL-2R γc for associating with human or mouse IL-4Rα to generate a signaling type I IL-4R is conserved.56 The murine IL-2R γc can complex with either human or murine IL-4Rα to create a functional type I IL-4R. In contrast, this is not the case for IL-13Rα1. Exploitation of this species specificity might aid in the identification of the epitope or epitopes required for the IL-13Rα1/IL-4Rα interaction. Pharmaceuticals targeted specifically to the target residue or residues would allow specific inhibition of IL-13 function while leaving IL-4 signaling intact and might prove beneficial in the treatment of atopic disorders.

IL-13Rα1 is widely expressed and has been demonstrated on nearly every cell tested except human or mouse T cells and mouse B cells, which is consistent with the known functions of IL-13.57, 58, 59, 60 On human B cells, expression of IL-13Rα1 has been reported to be modulated by means of activation through CD40 ligand or surface immunoglobulin.57, 61

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IL-13Rα2 

The cDNA for human IL-13Rα2 encodes a 380-amino-acid protein including a 26-amino-acid signal sequence.52 It shares 59% amino acid identity with its mouse counterpart.62 IL-13Rα2 transcripts have been found in the spleen, liver, lung, thymus, and brain.52, 62 As described above, expression of IL-13Rα1 and IL-4Rα together is sufficient to render cells responsive to IL-13, and thus IL-13Rα2 is not required for IL-13 function. Expression of IL-13Rα2 in vitro resulted in high-affinity binding of IL-13 (Kd = 250 pmol/L) but was insufficient to render cells responsive to IL-13, even in the presence of IL-4Rα.62 This has led to speculation that IL-13Rα2 is a decoy receptor. This has been further supported by the finding that IL-13Rα2 has been found in soluble form in vivo,51 and its overexpression might diminish IL-13 signaling.63, 64 However, the biologic role of IL-13Rα2 is still not clear. Generation and characterization of IL-13Rα2 gene-targeted mice will be useful in understanding the function of this receptor.

Recently, IL-13Rα2 was shown to exist largely as an intracellular molecule. Large pools of IL-13Rα2 were found intracellularly in cultured monocytes, respiratory epithelial cells, primary respiratory epithelium, and primary human monocytes, supporting that this observation is not restricted to a given cell type but rather appears to be widespread.64 This intracellular pool was rapidly mobilized to the cell surface after treatment of cells with IFN-γ. Furthermore, IFN-γ–dependent upregulation of IL-13Rα2 was associated with diminished IL-13 signaling, supporting the hypothesis that IL-13Rα2 acts as a decoy receptor that can regulate IL-13 responses. This represents a novel mechanism by which IFN-γ can regulate IL-13 responses.

Thus the receptor complexes for IL-4 and IL-13 are intertwined systems that are likely regulated at multiple levels, including by differential levels of expression of the various components, by preferential association of certain components, or both.

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IL-13 Signaling 

Consistent with the fact that IL-4 and IL-13 share common subunits, they also share common signaling pathways. Studies in STAT6-deficient mice have revealed that IL-13 signaling uses the JAK–signal transducer and activator of transcription (STAT) pathway and specifically STAT6.65, 66 Signaling through IL-4Rα/IL-13Rα1 is thought to occur through IL-4Rα because both IL-4 and IL-13 stimulation of the complex results in activation of signaling intermediates characteristic of IL-4 responses, including phosphorylation of IL-4Rα, insulin receptor substrate 2 (IRS-2), JAK1, and Tyk2.28, 67 IL-4Rα contains 5 conserved tyrosine residues, Y497, Y575, Y603, Y631, and Y713, which are all important in signaling through this receptor. Structure-function analyses have revealed that Y497 is part of the IL-4R motif that is necessary for the recruitment of IRS-1 and IRS-2 to IL-4Rα after IL-4 stimulation and is critical for IL-4–dependent cell proliferation.68 The tyrosines Y575, Y603, and Y631 can act as STAT6 docking sites, and as long as one of the 3 tyrosines remains intact, IL-4–dependent gene induction remains intact.56 Tyrosine 713 is part of an immunotyrosine-based inhibitory motif (ITIM) and was recently shown to be important in the negative regulation of IL-4 and IL-13 responses.69 We will now review the signaling pathways activated by IL-13.

JAK/STAT pathway 

JAKs are tyrosine kinases that each contains a true catalytic domain and a pseudokinase domain. There are 4 JAKs: JAK1, JAK2, JAK3, and Tyk2. JAK1, JAK2, and Tyk2 are ubiquitously expressed, whereas JAK3 expression is limited to hematopoietic cells.6 IL-4Rα, γc, and IL-13Rα1 all contain proline-rich Box-1 regions that bind JAK1, JAK3, and Tyk2, respectively. In hematopoietic cells that express γc and the associated JAK3, IL-4 binding results in activation of JAK1 and JAK3.70, 71 In contrast, in nonhematopoietic cells IL-4 treatment results in phosphorylation of JAK1 and Tyk2.72, 73 This is because in the absence of γc, IL-4 uses the type II receptor, and IL-13Rα1 binds Tyk2. IL-13 results in activation of JAK1 and Tyk2 in hematopoietic and nonhematopoietic cells.67, 74, 75 Activation of JAKs results in phosphorylation of the cytoplasmic tyrosines in IL-4Rα, leading to the recruitment of STAT6 to the receptor, followed by STAT6 phosphorylation and activation.

Activation of STAT6 after receptor engagement involves multiple steps and is dependent on critical structural elements within STAT6. First, association of STAT6 with tyrosine-phosphorylated regions of cytokine receptors occurs through its SH2 domain. Subsequently, STAT6 is phosphorylated on Y641, a residue critical for STAT6 function,76 and phosphorylated STAT6 monomers dimerize through their respective amino terminal domains, with Y641 of one monomer associating with the SH2 domain of the other.77 Activated STAT6 dimers then translocate to the nucleus, bind specific canonic DNA elements, and initiate transcription of downstream genes. The crystal structure of STAT1-DNA complexes revealed that dimeric interactions between the 2 respective SH2 domains and C-terminal phosphotyrosines were critical for the formation of the DNA-binding region.78 In the presence of IL-4 or IL-13, STAT6 activation is maintained indefinitely,79, 80 and it has been shown that maintenance of STAT6 activity requires ongoing JAK activity and a continuous cycle of activation, deactivation, nuclear export, and reactivation.80

The nuclear import requirements for the STAT proteins remain to be identified. Nuclear localization occurs both at the level of nuclear import and nuclear export.81 No nuclear localization signals have been identified in the STATs; however, a recent report revealed the importance of a leucine-rich nuclear export signal (NES) in STAT1.82 NES-mediated nuclear export is mediated through the NES receptor, which was identified as the chromosome maintenance (Crm1) gene.83, 84 In a recent study nuclear export was shown to be necessary for maintenance of STAT6 activation.80

Some STAT molecules, including STAT1, STAT4, and STAT5, can form tetramers through their N-terminal domains, allowing higher affinity binding to recognition sequences in tandem 6. A conserved Trp residue in the N domain is important for tetramer formation. Tetramer formation has not been demonstrated for STAT6.

IRS-1/IRS-2 pathway 

IRS-1 and a homologous protein, IRS-2 (also known as 4-phosphotyrosine substrate), are recruited to phosphorylated Y497 of IL-4Rα after ligand binding, leading to phosphorylation and activation of IRS-1 and IRS-2.85 IRS-1 binds to homologous sequences in the intracellular domains of the insulin and insulin growth factor receptors, and these sequences were found to be critical for signaling.86 Similarly, when Y497 was mutated or the surrounding motif was deleted, IRS-1 was not recruited to IL-4Rα and was not phosphorylated.68 The cells expressing this mutant IL-4Rα also displayed a markedly diminished proliferative response to IL-4. Thus Y497 is important for IL-4– and IL-13–dependent proliferation.

Two pathways have been implicated in signaling downstream of IRS-1 and IRS-2: the phosphoinositol 3 (PI3) kinase and Ras/mitogen-activated protein kinase pathways.85 After cytokine stimulation, IRS-1 and IRS-2 are phosphorylated and are able to interact with the p85α subunit of PI3 kinase. The importance of the PI3 kinase in cell proliferation has been further supported by experiments with wortmannin, an inhibitor of PI3 kinase that demonstrated that inhibition of PI3 kinase blocked IL-4–mediated cell survival.87 Phosphorylated IRS-1 and IRS-2 also interact with the adaptor protein Grb-2, which associates with SOS, a Ras activator.88 The role of the mitogen-activated protein kinase pathway in IL-4Rα–mediated signaling is not clear.

Role of IL-13Rα1 and IL-13Rα2 in IL-13 signaling 

The precise roles of IL-13Rα1 and IL-13Rα2 in IL-13 signaling and response are not clear. As described above, Tyk2 binds to the box region of IL-13Rα1; however, IL-13Rα1 might have additional yet unknown signaling function. A truncated murine IL-13Rα1 lacking the intracellular domain was not able to mediate IL-13–induced signals or responses, supporting the possibility that IL-13Rα1 is required for signaling.89 The cytoplasmic domain of human IL-13Rα1 contains 2 tyrosine residues, Y402 and Y405, which might serve as docking sites for additional signaling intermediates. These tyrosines have been shown to be docking sites for STAT3 in vitro, although the biologic relevance of this observation remains to be demonstrated because Y to F mutant IL-13Rα1 receptors mediated IL-13–dependent signaling and growth.90, 91 Other studies have failed to find activated STAT3 in the nucleus after IL-4 or IL-13 treatment of cells.92 Nevertheless, it is striking that the intracellular domain (60 amino acids in length) of IL-13Rα1 is greater than 98% conserved between human patients and mice, differing by only 3 amino acids, and 2 of these 3 differences are conservative changes. This argues that the IL-13Rα1 intracellular domain has an important biologic function. It is possible that the function of the intracellular IL-13Rα1 domain is to allow effective coupling with the signaling IL-4Rα chain. The heterodimeric interaction between IL-13Rα1 and IL-4Rα is species specific (ie, human IL-13Rα1 can only associate with IL-4Rα and not murine IL-4Rα),55 and thus the epitopes on IL-13Rα1 responsible for binding IL-4Rα must be distinct between the 2 species. Because the human and mouse IL-13Rα1 intracellular domains are nearly identical, these epitopes likely occur in the extracellular domain.

Recently, there is some evidence that IL-13 might have effects that are independent of IL-4Rα, suggesting the presence of another distinct IL-13 receptor or receptor subunit.93 Intracellular regions of IL-13Rα1 might serve as docking sites for association of IL-13Rα1 with yet unidentified IL-13 receptors, signaling intermediates, or both or, alternatively, with the other known IL-13 receptor, IL-13Rα2. It is currently not known whether IL-13Rα1 and IL-13Rα2 form a physiologic complex.

As discussed above, IL-13Rα2 is thought to act as a decoy receptor because expression of IL-13Rα2 in vitro resulted in high-affinity IL-13 binding but was insufficient to render cells responsive to IL-13, even in the presence of IL-4Rα.62 IL-13Rα2 has a short cytoplasmic tail (17 amino acids in the human subject) that contains no Box-1 or Box-2 signaling motifs, supporting the hypothesis that it has no signaling function. Both human and murine IL-13Rα2 contain a tyrosine residue in their respective short intracellular domains, but no signaling role has yet been identified for this tyrosine. Recently, it was demonstrated that IL-13Rα2 can mediate internalization of IL-13 independent of IL-13 signaling63 and that this internalization is dependent on a dileucine motif in the transmembrane domain.94

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Regulation of IL-13 signaling: regulation of the JAK/STAT pathway 

Although STAT6 activation in response to IL-4 and IL-13 has been well documented, the molecular mechanisms responsible for the termination of JAK/STAT signaling remain poorly understood. A number of negative regulators of the JAK/STAT signaling pathway have been described, including SH2-containing phosphatases, suppressors of cytokine signaling (SOCS), and protein inhibitors of activated STAT of transcription (PIAS). These are shown schematically in Fig 3.

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  • Fig. 3. 

    Mechanisms to downregulate IL-13–induced JAK/STAT activation. A, SHP. SH2-domain containing tyrosine phosphatases (SHP) downregulate IL-13 signaling by dephosphorylating activated JAKs and STATs. B, SOCS. Expression of SOCS proteins is induced by cytokine, and then SOCSs bind and inhibit JAKs. They might target the JAKs for proteasomal degradation. C, PIAS. Although no PIAS has been yet described for STAT6, PIAS proteins bind to activated STAT dimers and inhibit DNA binding. The schematic overview is based on published observations with STAT1. [A larger version of this illustration is available in the online Journal at (www.mosby.com/jaci ).]

SH2-containing phosphatases 

SH2 domain–containing tyrosine phosphatase 1 (SHP-1) is an intracellular protein tyrosine phosphatase that is widely expressed in hematopoietic cells. It has been shown to be involved in the negative regulation of multiple cytokine receptors, including erythropoietin, IL-2, IL-3, CSF, and IL-4Rα,95, 96, 97, 98, 99, 100, 101 SHP-1 has been shown to associate with IL-4Rα100, 102 and recently was shown to negatively regulate IL-4 responses in pre–B-cell lines derived from me/me mice.101 Furthermore, nonspecific inhibition of tyrosine phosphatase activity resulted in constitutive activation of JAK1 and STAT6, supporting a role for phosphatases in the negative regulation of the pathway.103 In addition, overexpression of SHP-1 resulted in reduced IL-4–dependent STAT6 activation.101 Studies have demonstrated an association of SHP-1 and SHP-2 with the IL-4Rα chain.100, 102 The mechanisms by which these phosphatases inhibit JAK/STAT signaling are unclear. They might bind to receptors and act on STATs, as recently suggested.69 Alternatively, SHP-1 has been shown to bind JAK2 directly,97 suggesting that the phosphatase acts directly on JAKs.

The ITIM motif I/VxYxxL has been identified in a growing family of inhibitory receptors and plays a critical role in negative regulation of signaling through the receptors.104 Recently, the sequence containing Y713 in the IL-4Rα chain was identified as a functional ITIM.69 SHP-1, SHP-2, and SH2-containing inositol phosphatase were all shown to interact with the Y713 putative ITIM sequence, and ablation of this sequence resulted in an enhanced proliferative response to IL-4. The mechanism of this is still unclear because the activation of JAK1 and IRS-2 were not affected by ablation of the ITIM Y713.69

Suppressor of cytokine signaling 

The first member of this family, cytokine-inducible SH2-containing protein (CIS), was discovered as an immediate early gene induced by multiple cytokines.105 SOCS proteins were discovered by 3 groups using distinct approaches to search for proteins capable of inhibiting cytokine responses,106 interacting with JAKs,107 and containing homology to STAT SH2 domains.108 Thus SOCSs are also known as JAK2-binding protein, STAT-induced STAT inhibitor, and CIS. There are now 8 members of this family, SOCSs 1 through 7 and CIS, and their expression profiles vary.109 SOCS proteins form a negative feedback loop whereby SOCS genes are induced after cytokine stimulation and inhibit cytokine signaling.110, 111, 112 An important feature of SOCS-mediated regulation is that it inhibits multiple pathways, and there is considerable cross-talk.109, 110 For example, when SOCS-1 is overexpressed in cell lines, it inhibits STAT activation by several cytokines, including IL-4.113 IFN-γ antagonizes many of the activities of IL-4 and IL-13, and this is mediated by SOCS-1 in a STAT1-dependent fashion.111, 112 However, characterization of SOCS-1 null mice has shown that SOCS-1 is also a critical regulator of IFN-γ responsiveness.114 Thus SOCS-1 is important in the cross-talk between IFN-γ and the IL-4 and IL-13 pathways.

SOCS-1 has been shown to bind and inhibit JAKs,110 but this might not be true of all SOCS family members. The mechanisms by which the SOCSs function are still not clear. Each of the SOCSs contains an N-terminal domain, a central SH2 domain, and a C-terminal SOCS box, which mediates binding to elongin B/C.115, 116 It has been hypothesized that binding of elongin B/C to SOCSs might target SOCSs and any associated proteins (eg, JAKs) to the proteasome for degradation.116, 117 A recent study provided further evidence for this hypothesis, whereby SOCS-mediated inhibition of cytokine signaling required an active proteasomal degradation pathway.118

Protein inhibitor of activated STAT 

Another important family of proteins in the regulation of the JAK/STAT pathway is the PIAS family of proteins, which have recently been described and have specificity for some STAT family members.119, 120 These proteins bind specifically to phosphorylated STAT dimers and prevent them from binding DNA.121 The PIAS proteins are constitutively expressed, and little is known about their regulation. However, recent studies have demonstrated that STAT1 function is modulated by means of methylation of a critical arginine residue at position 31.122 Arg31 is conserved among the STAT molecules, and methylation is likely generally important for STAT function. The mechanism of this methylation-dependent modulation appears to be regulation at the level of STAT1-PIAS1 association. PIAS1 binds to STAT1 dimers and prevents STAT1 DNA binding. Methylation of STAT1 reduces the ability of it to associate with PIAS and thus increases STAT1 DNA-binding activity.122 No PIAS has yet been identified for STAT6, the STAT activated by IL-4 and IL-13.

Several possibilities exist as to the fate of an activated STAT6 molecule once it has completed its role in IL-4– or IL-13–dependent signal transduction. One possibility is that STAT6 is ubiquinated and regulated by means of proteasomal degradation. Indeed, inhibitors of proteasome degradation have been shown to prolong STAT1 activation123, 124 and STAT6 activation.125 Thus a constant cycle of activation, degradation, and de novo protein synthesis might be required to maintain a prolonged STAT6 response. A second possibility is that activated STAT6 in the nucleus is deactivated by means of dephosphorylation through the action of a specific phosphatase. Several studies have implicated tyrosine phosphatases in the regulation of STAT signaling.124, 126, 127, 128 Consistent with this possibility, studies examining STAT1 have shown that activated STAT1 disappears from the nucleus within 60 minutes and that removal of the activated STAT1 is dependent on a protein tyrosine phosphatase.124 Recently, a nuclear isoform of T cell-protein phosphatase (also referred to as TcPTP) was identified as the tyrosine phosphatase responsible for STAT1 dephosphorylation in the nucleus.129 Interestingly, another recent study demonstrated that dephosphorylation of STAT1 by a nuclear isoform of T cell-protein phosphatase (or TcPTP) is regulated by arginine methylation of STAT1 and that this regulation is dependent on PIAS.130 These data are consistent with a model whereby methylation increases association of STAT1 with PIAS with a concomitant decrease in binding of STAT1 to TcPTP and thus delayed dephosphorylation of STAT1. Such a model would also implicate a specific nuclear protein tyrosine phosphatase in STAT6 deactivation. The deactivated STAT6 molecule could then be degraded or shuttled back to the cytoplasm, where it could be reactivated by means of tyrosine phosphorylation.

The multiple levels of regulation along the JAK/STAT activation cascade underscore the importance of this pathway, and it is likely that the degradation and recycling of these mediators is also tightly regulated.

Regulation of the IRS-1/IRS-2 pathway 

The IL-4Rα–associated kinase Fes131 was recently shown to be important in regulation of the IRS-1/IRS-2 pathway.132 Fes is a tyrosine kinase expressed in hematopoietic cells, and overexpression of kinase-inactive Fes blocks IL-4–dependent activation of IRS-2 and its downstream association with PI3 kinase but has no effect on STAT6 activation.132 Interestingly, Fes appears to be activated by JAK1 because Fes was not activated in JAK1-deficient cells. These data support a role for Fes as a signaling intermediate between JAK1 and phosphorylation of IRS-1 and IRS-2 and thus subsequent activation of PI3 kinase. Interestingly, Fes has also been implicated as a regulator of JAK/STAT signaling. STAT activation was enhanced in macrophages derived from c-fes−/− mice,133 suggesting that Fes might be a negative regulator of STAT.

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Genetic variants of IL-13 and IL-4Rα 

Genetic variants of IL-13 that are associated with asthma and atopy have been found both in the promoter and coding regions.134, 135, 136, 137 The coding variant results in a substitution of an arginine with a glutamine at position 130 (numbering includes the 20-amino-acid signal sequence). This variant has been found to be associated with asthma, increased IgE levels, and atopic dermatitis in Japanese and European populations.134, 136, 137 In a recent study the mechanism by which this variant might predispose to asthma was investigated.138 The investigators found that the IL-13 Q130 variant displayed somewhat enhanced stability compared with the wild-type IL-13 and that this might result from a slightly higher affinity of the IL-13 variant for IL-13Rα2. Consistent with these observations, they found higher median serum IL-13 levels in patients homozygous for the Q130 IL-13 variant when compared with nonhomozygous patients.

The gene encoding IL-4Rα represents an ideal candidate gene for atopy susceptibility because of its pivotal role in both IL-4 and IL-13 signaling, its key role in allergic inflammation by promoting IgE production and TH2 cell development, and its location on chromosome 16, which has been linked to asthma.139 Eight naturally occurring allelic variants of IL-4Rα have been reported,102, 140, 141, 142 and several of these have been associated with the prevalence of atopy102, 141, 142, 143 and the severity of asthma.144 Two of the allelic variants of the gene encoding IL-4Rα that have been associated in multiple studies with asthma and atopy are the I75V and Q576R polymorphisms (numbering including the 25-amino-acid signal peptide).102, 143 Both the Q576R and I75V polymorphisms are common and occur in combination in the general population, and thus it is important to examine the functional consequences of these polymorphisms alone and in combination. We recently reported that although neither the Q576R nor the I75V variants alone affected IL-4–dependent CD23 expression, the combination of V75R576 resulted in enhanced sensitivity to IL-4.145 Furthermore, the association of V75/R576 with atopic asthma was greater than that of either allele alone, and the association of R576 with atopic asthma was dependent on the coexist-ence of V75.

Thus it is critical to study the effects of snps in combination because the functional significance of a given snp might only be evident in a specific setting of additional snps in the same or different genes. Furthermore, small functional changes in gene products that act along a common pathway might have a significant effect. There is evidence for this from a recent genetic study demonstrating interactive genetic effects between snps in IL-4Rα and the IL-13 promoter.146 A relatively small change in the production of IL-13 caused by a promoter polymorphism coupled with a second small functional change in its receptor, IL-4Rα, might result in a combined change that is biologically significant, although neither alone is significant. Additional studies examining the functional and genetic contributions of multiple snps in series acting on a common pathway are needed to further our understanding of these events.

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IL-13 receptor/signaling pathways as a target for therapeutic intervention 

IL-13 regulates a variety of functions in hematopoietic and nonhematopoietic cells and has been shown in clinical studies to be associated with the development of atopic disorders, including atopic dermatitis,147, 148 allergic rhinitis,149 and asthma.150, 151, 152, 153 It has been demonstrated to play a pathogenic role in the development of bronchial asthma independent of IL-4.32, 33, 34 Thus IL-13 and its receptor and signaling pathways are an attractive target for immunotherapy. Currently, studies are underway to evaluate the clinical potential of IL-13 antagonists, including soluble IL-13Rα2. The optimal strategy would be to block IL-13, but not IL-4, responses. IL-13 receptors are also expressed on a variety of tumor cell lines,154, 155 and IL-13 has been implicated in the pathogenesis of malignancies, such as Hodgkin disease, in which IL-13 acts as an autocrine growth factor for Reed-Sternberg tumor cells.156 Thus IL-13 antagonists might also be useful in the treatment of malignancies.

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Conclusions 

IL-13 is a critical mediator of allergic inflammation and contributes directly to airway hyperreactivity. As such, it is one of the most attractive, novel potential targets for therapeutic intervention in the treatment of asthma. Studies are already underway evaluating soluble IL-13 receptors. Although much is now known about this cytokine and its signaling pathways, as discussed in this review, important pieces of the puzzle remain unknown. One of the biggest questions that remains is how IL-13 induces the effects that IL-4 does not. Because both IL-4 and IL-13 transmit their signals through the IL-4Rα, the mechanism by which IL-13 results in downstream effects that are not observed with IL-4 is a mystery. It is possible that additional IL-13–specific signaling molecules or receptor proteins exist. Alternatively, differences in IL-4 and IL-13 effects might be due to differences in the kinetics of their production or half-lives locally. Finally, the function of IL-13Rα2 is still unclear, and this receptor might play a yet unrecognized role in IL-13 signaling. Identification of the mechanisms that account for the IL-13 effects that are not seen with IL-4 will allow the development of compounds to target IL-13 independently of IL-4. Furthermore, this information will allow investigators to better evaluate potential drugs. In any case, it is clear that the intense ongoing investigation in this field will likely yield exciting new targets for therapy for allergy and immunology patients.

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Acknowledgements 

Connie Petitt is appreciated for secretarial support and Jesus R. Guajardo, MD, for assistance with Fig 2.

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References 

  1. Brown KD, Zurawski SM, Mosmann TR, Zurawski G. A family of small inducible proteins secreted by leukocytes are members of a new superfamily that includes leukocyte and fibroblast-derived inflammatory agents, growth factors, and indicators of various activation processes. J Immunol. 1989;142:679–687
  2. Minty Z, Chalon P, Derocq JM, Dumont X, Guillemot JC, Kaghad M, et al.  Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature. 1993;362:248–250
  3. Morgan J, Dolganov G, Robbins S, Hinton L, Lovett M. The selective isolation of novel cDNA's encoded by the regions surrounding the human interleukin-4 and 5 genes. Nucleic Acids Res. 1992;20:5173–5179
  4. McKenzie A, Culpepper J, de Waal Malefyt R, Briere F, Punnonen J, Aversa G, et al.  Interleukin 13, a T-cell derived cytokine that regulates human monocyte and B-cell function. Proc Natl Acad Sci U S A. 1993;90:3735–3739
  5. de Vries JE. Molecular and biological characteristics of interleukin-13. Chem Immunol. 1996;63:204–218
  6. Leonard WJ, Lin JX. Cytokine receptor signaling pathways. J Allergy Clin Immunol. 2000;105:877–888
  7. Chomarat P, Banchereau J. Interleukin-4 and interleukin-13: their similarities and discrepancies. Int Rev Immunol. 1998;17:1–52
  8. Hage T, Sebald W, Reinemer P. Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface. Cell. 1999;97:271–281
  9. Powers R, Garrett DS, March CJ, Frieden EA, Gronenborn AM, Clore GM. Three-dimensional solution structure of human interleukin-4 by multidimensional heteronuclear magnetic resonance spectroscopy. Science. 1992;256:1673–1677
  10. Tsarbopoulos A, Varnerin J, Cannon-Carlson S, Wylie D, Pramanik B, Tang J, et al.  Mass spectrometric mapping of disulfide bonds in recombinant human interleukin-13. J Mass Spectrom. 2000;35:446–453
  11. Park LS, Friend D, Sassenfeld HM, Urdal DL. Characterization of the human B cell stimulatory factor 1 receptor. J Exp Med. 1987;166:476–488
  12. Smirnov DV, Smirnova MG, Korobko VG, Frolova EI. Tandem arrangement of human genes for interleukin-4 and interleukin-13: resemblance in their organization. Gene. 1995;155:277–281
  13. Marsh DG, Neely JD, Breazeale DR, Ghosh B, Friedhoff LR, Ehrlich-Kautzky E, et al.  Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science. 1994;264:1152–1156
  14. Meyers DA, Postma DS, Panhuysen CI, Xu J, Amelung PJ, Levitt RC, et al.  Evidence for a locus regulating total serum IgE levels mapping to chromosome 5. Genomics. 1994;23:464–470
  15. Postma DS, Bleecker ER, Amelung PJ, Holroyd KJ, Xu J, Panhuysen CI, et al.  Genetic susceptibility to asthma—bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med. 1995;333:894–900
  16. Daniels SE, Bhattacharrya S, James A, Leaves NI, Young A, Hill MR, et al.  A genome-wide search for quantitative trait loci underlying asthma. Nature. 1996;383:247–250
  17. Oettgen HC, Geha RS. IgE regulation and roles in asthma pathogenesis. J Allergy Clin Immunol. 2001;107:429–440
  18. Zurawski G, de Vries JE. Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells. Immunol Today. 1994;15:19–26
  19. de Vries JE. The role of IL-13 and its receptor in allergy and inflammatory responses. J Allergy Clin Immunol. 1998;102:165–169
  20. Endo T, Ogushi F, Sone S. LPS-dependent cyclooxygenase-2 induction in human monocytes is down-regulated by IL-13, but not by IFN-gamma. J Immunol. 1996;156:2240–2246
  21. Doherty TM, Kastelein R, Menon S, Andrade S, Coffman RL. Modulation of murine macrophage function by IL-13. J Immunol. 1993;151:7151–7160
  22. Sozzani P, Cambon C, Vita N, Seguelas MH, Caput D, Ferrara P, et al.  Interleukin-13 inhibits protein kinase C-triggered respiratory burst in human monocytes. Role of calcium and cyclic AMP. J Biol Chem. 1995;270:5084–5088
  23. Lentsch AB, Shanley TP, Sarma V, Ward PA. In vivo suppression of NF-kappa B and preservation of I kappa B alpha by interleukin-10 and interleukin-13. J Clin Invest. 1997;100:2443–2448
  24. Horie S, Okubo Y, Hossain M, Sato E, Nomura H, Koyama S, et al.  Interleukin-13 but not interleukin-4 prolongs eosinophil survival and induces eosinophil chemotaxis. Intern Med. 1997;36:179–185
  25. Luttmann W, Knoechel B, Foerster M, Matthys H, Virchow JC, Kroegel C. Activation of human eosinophils by IL-13. Induction of CD69 surface antigen, its relationship to messenger RNA expression, and promotion of cellular viability. J Immunol. 1996;157:1678–1683
  26. Pope SM, Brandt EB, Mishra A, Hogan SP, Zimmermann N, Matthaei KI, et al.  IL-13 induces eosinophil recruitment into the lung by an IL-5- and eotaxin-dependent mechanism. J Allergy Clin Immunol. 2001;108:594–601
  27. Bochner BS, Klunk DA, Sterbinsky SA, Coffman RL, Schleimer RP. IL-13 selectively induces vascular cell adhesion molecule-1 expression in human endothelial cells. J Immunol. 1995;154:799–803
  28. Wills-Karp M. IL-12/IL-13 axis in allergic asthma. J Allergy Clin Immunol. 2001;107:9–18
  29. Roux M, Schachtschneider S, Schaefer T, Smola H, Solberg S, Krieg T. IL-13 induces type-1 collagen-synthesis in human dermal fibroblasts. J Invest Dermatol. 1994;103:444–449
  30. Li L, Xia Y, Nguyen A, Lai YH, Feng L, Mosmann TR, et al.  Effects of Th2 cytokines on chemokine expression in the lung: IL-13 potently induces eotaxin expression by airway epithelial cells. J Immunol. 1999;162:2477–2487
  31. Laoukili J, Perret E, Willems T, Minty A, Parthoens E, Houcine O, et al.  IL-13 alters mucociliary differentiation and ciliary beating of human respiratory epithelial cells. J Clin Invest. 2001;108:1817–1824
  32. Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, et al.  Interleukin-13: central mediator of allergic asthma. Science. 1998;282:2258–2261
  33. Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, et al.  Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest. 1999;103:779–788
  34. Grunig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, Rennick DM, et al.  Requirement for IL-13 independently of IL-4 in experimental asthma. Science. 1998;282:2261–2263
  35. Webb DC, McKenzie AN, Koskinen AM, Yang M, Mattes J, Foster PS. Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyperreactivity. J Immunol. 2000;165:108–113
  36. Yang M, Hogan SP, Henry PJ, Matthaei KI, McKenzie AN, Young IG, et al.  Interleukin-13 mediates airways hyperreactivity through the IL-4 receptor-alpha chain and STAT-6 independently of IL-5 and eotaxin. Am J Respir Cell Mol Biol. 2001;25:522–530
  37. Zheng T, Zhu Z, Wang Z, Homer RJ, Ma B, Riese RJ, et al.  Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema. J Clin Invest. 2000;106:1081–1093
  38. Finkelman FD, Wynn TA, Donaldson DD, Urban JF. The role of IL-13 in helminth-induced inflammation and protective immunity against nematode infections. Curr Opin Immunol. 1999;11:420–426
  39. Galizzi JP, Zuber CE, Harada N, Gorman DM, Djossou O, Kastelein R, et al.  Molecular cloning of a cDNA encoding the human interleukin 4 receptor. Int Immunol. 1990;2:669–675
  40. Idzerda RL, March CJ, Mosley B, Lyman SD, Vanden Bos T, Gimpel SD, et al.  Human interleukin 4 receptor confers biological responsiveness and defines a novel receptor superfamily. J Exp Med. 1990;171:861–873
  41. Aversa G, Punnonen J, Cocks BG, de Waal Malefyt R, Vega F, Zurawski SM, et al.  An interleukin 4 (IL-4) mutant protein inhibits both IL-4 or IL-13-induced human immunoglobulin G4 (IgG4) and IgE synthesis and B cell proliferation: support for a common component shared by IL-4 and IL-13 receptors. J Exp Med. 1993;178:2213–2218
  42. Kruse N, Tony HP, Sebald W. Conversion of human interleukin-4 into a high affinity antagonist by a single amino acid replacement. EMBO J. 1992;11:3237–3244
  43. Lefort S, Vita N, Reeb R, Caput D, Ferrara P. IL-13 and IL-4 share signal transduction elements as well as receptor components in TF-1 cells. FEBS Lett. 1995;366:122–126
  44. Zurawski SM, Chomarat P, Djossou O, Biduad C, McKenzie AN, Miossec P, et al.  The primary binding subunit of the human interleukin-4 receptor is also a component of the interleukin-13 receptor. J Biol Chem. 1995;270:13869–13878
  45. Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, et al.  Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993;73:147–157
  46. Matthews DJ, Clark PA, Herbert J, Morgan G, Armitage RJ, Kinnon C, et al.  Function of the interleukin-2 (IL-2) receptor gamma-chain in biologic responses of X-linked severe combined immunodeficient B cells to IL-2, IL-4, IL-13, and IL-15. Blood. 1995;85:38–42
  47. Aman MJ, Tayebi N, Obiri NI, Puri RK, Modi WS, Leonard WJ. cDNA cloning and characterization of the human interleukin 13 receptor alpha chain. J Biol Chem. 1996;271:29265–29270
  48. Caput D, Laurent P, Kaghad M, Lelias JM, Lefort S, Vita N, 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
  49. Hilton DJ, Zhang JG, Metcalf D, Alexander WS, Nicola NA, Willson TA. 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
  50. Miloux B, Laurent P, Bonnin O, Lupker J, Caput D, Vita N, 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
  51. Zhang JG, Hilton DJ, Willson TA, McFarlane C, Roberts BA, Moritz RL, 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
  52. Guo J, Apiou F, Mellerin MP, Lebeau B, Jacques Y, Minvielle S. Chromosome mapping and expression of the human interleukin-13 receptor. Genomics. 1997;42:141–145
  53. Obiri NI, Murata T, Debinski W, Puri RK. Modulation of interleukin (IL)-13 binding and signaling by the gammac chain of the IL-2 receptor. J Biol Chem. 1997;272:20251–20258
  54. 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
  55. Andrews R, Rosa L, Daines M, Khurana Hershey G. 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
  56. Ryan JJ, McReynolds LJ, Keegan A, Wang LH, Garfein E, Rothman P, et al.  Growth and gene expression are predominantly controlled by distinct regions of the human IL-4 receptor. Immunity. 1996;4:123–132
  57. Gauchat JF, Schlagenhauf E, Feng NP, Moser R, Yamage M, Jeannin P, 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
  58. Graber P, Gretener D, Herren S, Aubry JP, Elson G, Poudrier J, 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
  59. Akaiwa M, Yu B, Umeshita-Suyama R, Terada N, Suto H, Koga T, et al.  Localization of human interleukin 13 receptor in non-haematopoietic cells. Cytokine. 2001;13:75–84
  60. Murata T, Husain SR, Mohri H, Puri RK. 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
  61. Ogata H, Ford D, Kouttab N, King TC, Vita N, Minty A, et al.  Regulation of interleukin-13 receptor constituents on mature human B lymphocytes. J Biol Chem. 1998;273:9864–9871
  62. Donaldson DD, Whitters MJ, Fitz LJ, Neben TY, Finnerty H, Henderson SL, 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
  63. Kawakami K, Taguchi J, Murata T, Puri RK. The interleukin-13 receptor alpha2 chain: an essential component for binding and internalization but not for interleukin-13-induced signal transduction through the STAT6 pathway. Blood. 2001;97:2673–2679
  64. 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
  65. Takeda K, Kamanaka M, Tanaka T, Kishimoto T, Akira S. Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice. J Immunol. 1996;157:3220–3222
  66. Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996;4:313–319
  67. Welham MJ, Learmonth L, Bone H, Schrader JW. Interleukin-13 signal transduction in lymphohemopoietic cells. Similarities and differences in signal transduction with interleukin-4 and insulin. J Biol Chem. 1995;270:12286–12296
  68. Keegan AD, Nelms K, White M, Wang LM, Pierce JH, Paul WE. An IL-4 receptor region containing an insulin receptor motif is important for IL-4-mediated IRS-1 phosphorylation and cell growth. Cell. 1994;76:811–820
  69. Kashiwada M, Giallourakis CC, Pan PY, Rothman PB. Immunoreceptor tyrosine-based inhibitory motif of the IL-4 receptor associates with SH2-containing phosphatases and regulates IL-4-induced proliferation. J Immunol. 2001;167:6382–6387
  70. Miyazaki T, Kawahara A, Fujii H, Nakagawa Y, Minami Y, Liu ZJ, et al.  Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science. 1994;266:1045–1047
  71. Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, et al.  Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science. 1994;266:1042–1045
  72. Murata T, Noguchi PD, Puri RK. IL-13 induces phosphorylation and activation of JAK2 Janus kinase in human colon carcinoma cell lines: similarities between IL-4 and IL-13 signaling. J Immunol. 1996;156:2972–2978
  73. Wang HY, Zamorano J, Yoerkie JL, Paul WE, Keegan AD. The IL-4-induced tyrosine phosphorylation of the insulin receptor substrate is dependent on JAK1 expression in human fibrosarcoma cells. J Immunol. 1997;158:1037–1040
  74. Keegan AD, Johnston JA, Tortolani PJ, McReynolds LJ, Kinzer C, O'Shea JJ, et al.  Similarities and differences in signal transduction by interleukin 4 and interleukin 13: analysis of Janus kinase activation. Proc Natl Acad Sci U S A. 1995;92:7681–7685
  75. Roy B, Cathcart MK. Induction of 15-lipoxygenase expression by IL-13 requires tyrosine phosphorylation of Jak2 and Tyk2 in human monocytes. J Biol Chem. 1998;273:32023–32029
  76. Mikita T, Campbell D, Wu P, Williamson K, Schindler U. Requirements for interleukin-4-induced gene expression and functional characterization of Stat6. Mol Cell Biol. 1996;16:5811–5820
  77. Mikita T, Daniel C, Wu P, Schindler U. Mutational analysis of the STAT6 SH2 domain. J Biol Chem. 1998;273:17634–17642
  78. Chen X, Vinkemeier U, Zhao Y, Jeruzalmi D, Darnell JE, Kuriyan J. Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell. 1998;93:827–839
  79. Wang HY, Shelburne CP, Zamorano J, Kelly AE, Ryan JJ, Keegan AD. Cutting edge: effects of an allergy-associated mutation in the human IL-4R alpha (Q576R) on human IL-4-induced signal transduction. J Immunol. 1999;162:4385–4389
  80. Andrews RP, Ericksen MB, Cunningham CM, Daines MO, Hershey GK. Analysis of the life cycle of Stat6. Continuous cycling of STAT6 is required for IL-4 signaling. J Biol Chem. 2002;277:36563–36569
  81. Ullman KS, Powers MA, Forbes DJ. Nuclear export receptors: from importin to exportin. Cell. 1997;90:967–970
  82. Mowen K, David M. Regulation of STAT1 nuclear export by Jak1. Mol Cell Biol. 2000;20:7273–7281
  83. Fornerod M, Ohno M, Yoshida M, Mattaj IW. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell. 1997;90:1051–1060
  84. Stade K, Ford CS, Guthrie C, Weis K. Exportin 1 (Crm1p) is an essential nuclear export factor. Cell. 1997;90:1041–1050
  85. Jiang H, Harris MB, Rothman P. IL-4/IL-13 signaling beyond JAK/STAT. J Allergy Clin Immunol. 2000;105:1063–1070
  86. White MF, Livingston JN, Backer JM, Lauris V, Dull TJ, Ullrich A, et al.  Mutation of the insulin receptor at tyrosine 960 inhibits signal transmission but does not affect its tyrosine kinase activity. Cell. 1988;54:641–649
  87. Zamorano J, Wang HY, Wang LM, Pierce JH, Keegan AD. IL-4 protects cells from apoptosis via the insulin receptor substrate pathway and a second independent signaling pathway. J Immunol. 1996;157:4926–4934
  88. White MF. The IRS-signaling system: a network of docking proteins that mediate insulin and cytokine action. Recent Prog Horm Res. 1998;53:119–138
  89. Orchansky PL, Ayres SD, Hilton DJ, Schrader JW. An interleukin (IL)-13 receptor lacking the cytoplasmic domain fails to transduce IL-13-induced signals and inhibits responses to IL-4. J Biol Chem. 1997;272:22940–22947
  90. Orchansky PL, Kwan R, Lee F, Schrader JW. Characterization of the cytoplasmic domain of interleukin-13 receptor-alpha. J Biol Chem. 1999;274:20818–20825
  91. Umeshita-Suyama R, Sugimoto R, Akaiwa M, Arima K, Yu B, Wada 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
  92. Wery-Zennaro S, Letourneur M, David M, Bertoglio J, Pierre J. 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
  93. Mattes J, Yang M, Siqueira A, Clark K, MacKenzie J, McKenzie AN, et al.  IL-13 induces airways hyperreactivity independently of the IL-4R alpha chain in the allergic lung. J Immunol. 2001;167:1683–1692
  94. 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
  95. Yi T, Mui AL, Krystal G, Ihle JN. Hematopoietic cell phosphatase associates with the interleukin-3 (IL-3) receptor beta chain and down-regulates IL-3-induced tyrosine phosphorylation and mitogenesis. Mol Cell Biol. 1993;13:7577–7586
  96. Chen HE, Chang S, Trub T, Neel BG. Regulation of colony-stimulating factor 1 receptor signaling by the SH2 domain-containing tyrosine phosphatase SHPTP1. Mol Cell Biol. 1996;16:3685–3697
  97. Klingmuller U, Lorenz U, Cantley LC, Neel BG, Lodish HF. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell. 1995;80:729–738
  98. Paulson RF, Vesely S, Siminovitch KA, Bernstein A. Signalling by the W/Kit receptor tyrosine kinase is negatively regulated in vivo by the protein tyrosine phosphatase Shp1. Nat Genet. 1996;13:309–315
  99. Gelderloos JA, Anderson SM. Over-expression of protein tyrosine phosphatase 1 (PTP1) alters IL-3-dependent growth and tyrosine phosphorylation. Oncogene. 1996;13:2367–2378
  100. Imani F, Rager KJ, Catipovic B, Marsh DG. Interleukin-4 (IL-4) induces phosphatidylinositol 3-kinase (p85) dephosphorylation. Implications for the role of SHP-1 in the IL-4-induced signals in human B cells. J Biol Chem. 1997;272:7927–7931
  101. Haque SJ, Harbor P, Tabrizi M, Yi T, Williams BR. Protein-tyrosine phosphatase Shp-1 is a negative regulator of IL-4- and IL-13-dependent signal transduction. J Biol Chem. 1998;273:33893–33896
  102. Khurana Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA. Association of atopy with a gain-of-function mutation in the interleukin-4 receptor a chain. N Engl J Med. 1997;337:1720–1725
  103. Haque SJ, Wu Q, Kammer W, Friedrich K, Smith JM, Kerr IM, et al.  Receptor-associated constitutive protein tyrosine phosphatase activity controls the kinase function of JAK1. Proc Natl Acad Sci U S A. 1997;94:8563–8568
  104. Reichel M, Nelson BH, Greenberg PD, Rothman PB. The IL-4 receptor alpha-chain cytoplasmic domain is sufficient for activation of JAK-1 and STAT6 and the induction of IL-4-specific gene expression. J Immunol. 1997;158:5860–5867
  105. Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, et al.  A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. EMBO J. 1995;14:2816–2826
  106. Starr R, Willson TA, Viney EM, Murray LJ, Rayner RJ, Jenkins BJ, et al.  A family of cytokine-inducible inhibitors of signalling. Nature. 1997;387:917–921
  107. Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamato H, Mitsui K, et al.  A new protein containing an SH2 domain that inhibits JAK kinases. Nature. 1997;387:921–924
  108. Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, Aono A, et al.  Structure and function of a new STAT-induced STAT inhibitor. Nature. 1997;387:924–929
  109. Greenhalgh CJ, Hilton DJ. Negative regulation of cytokine signaling. J Leukoc Biol. 2001;70:348–356
  110. Chen XP, Losman JA, Rothman P. SOCS proteins, regulators of intracellular signaling. Immunity. 2000;13:287–290
  111. Venkataraman C, Leung S, Salvekar A, Mano H, Schindler U. Repression of IL-4-induced gene expression by IFN-gamma requires Stat1 activation. J Immunol. 1999;162:4053–4061
  112. Losman JA, Chen XP, Hilton D, Rothman P. Cutting edge: SOCS-1 is a potent inhibitor of IL-4 signal transduction. J Immunol. 1999;162:3770–3774
  113. Yasukawa H, Sasaki A, Yoshimura A. Negative regulation of cytokine signaling pathways. Annu Rev Immunol. 2000;18:143–164
  114. Naka T, Tsutsui H, Fujimoto M, Kawazoe Y, Kohzaki H, Morita Y, et al.  SOCS-1/SSI-1-deficient NKT cells participate in severe hepatitis through dysregulated cross-talk inhibition of IFN-gamma and IL-4 signaling in vivo. Immunity. 2001;14:535–545
  115. Kamura T, Sato S, Haque D, Liu L, Kaelin WG, Conaway RC, et al.  The elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families. Genes Dev. 1998;12:3872–3881
  116. Zhang JG, Farley A, Nicholson SE, Willson TA, Zugaro LM, Simpson RJ, et al.  The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation. Proc Natl Acad Sci U S A. 1999;96:2071–2076
  117. Narazaki M, Fujimoto M, Matsumoto T, Morita Y, Saito H, Kajita T, et al.  Three distinct domains of SSI-1/SOCS-1/JAB protein are required for its suppression of interleukin 6 signaling. Proc Natl Acad Sci U S A. 1998;95:13130–13134
  118. Ram PA, Waxman DJ. Role of the cytokine-inducible SH2 protein CIS in desensitization of STAT5b signaling by continuous growth hormone. J Biol Chem. 2000;275:39487–39496
  119. Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, et al.  Specific inhibition of Stat3 signal transduction by PIAS3. Science. 1997;278:1803–1805
  120. Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, et al.  Inhibition of Stat1-mediated gene activation by PIAS1. Proc Natl Acad Sci U S A. 1998;95:10626–10631
  121. Liao J, Fu Y, Shuai K. Distinct roles of the NH2- and COOH-terminal domains of the protein inhibitor of activated signal transducer and activator of transcription (STAT) 1 (PIAS1) in cytokine-induced PIAS1-Stat1 interaction. Proc Natl Acad Sci U S A. 2000;97:5267–5272
  122. Mowen KA, Tang J, Zhu W, Schurter BT, Shuai K, Herschmann HR, et al.  Arginine methylation of STAT1 modulates IFNalpha/beta-induced transcription. Cell. 2001;104:731–741
  123. Kim TK, Maniatis T. Regulation of interferon-gamma-activated STAT1 by the ubiquitin-proteasome pathway. Science. 1996;273:1717–1719
  124. Haspel RL, Salditt-Georgieff M, Darnell JE. The rapid inactivation of nuclear tyrosine phosphorylated Stat1 depends upon a protein tyrosine phosphatase. EMBO J. 1996;15:6262–6268
  125. Wang D, Moriggl R, Stravopodis D, Carpino N, Marine JC, Teglund S, et al.  A small amphipathic alpha-helical region is required for transcriptional activities and proteasome-dependent turnover of the tyrosine-phosphorylated Stat5. EMBO J. 2000;19:392–399
  126. David M, Grimley PM, Finbloom DS, Larner AC. A nuclear tyrosine phosphatase downregulates interferon-induced gene expression. Mol Cell Biol. 1993;13:7515–7521
  127. Haque SJ, Flati V, Deb A, Williams BR. Roles of protein-tyrosine phosphatases in Stat1 alpha-mediated cell signaling. J Biol Chem. 1995;270:25709–25714
  128. Shuai K, Liao J, Song MM. Enhancement of antiproliferative activity of gamma interferon by the specific inhibition of tyrosine dephosphorylation of Stat1. Mol Cell Biol. 1996;16:4932–4941
  129. ten Hoeve J, de Jesus Ibarra-Sanchez M, Fu Y, Zhu W, Tremblay M, David M, et al.  Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol Cell Biol. 2002;22:5662–5668
  130. Zhu W, Mustelin T, David M. Arginine methylation of STAT1 regulates its dephosphorylation by T cell protein tyrosine phosphatase. J Biol Chem. 2002;277:35787–35790
  131. Izuhara K, Feldman RA, Greer P, Harada N. Interaction of the c-fes proto-oncogene product with the interleukin-4 receptor. J Biol Chem. 1994;269:18623–18629
  132. Jiang H, Foltenyi K, Kashiwada M, Donahue L, Vuong B, Hehn B, et al.  Fes mediates the IL-4 activation of insulin receptor substrate-2 and cellular proliferation. J Immunol. 2001;166:2627–2634
  133. Hackenmiller R, Kim J, Feldman RA, Simon MC. Abnormal Stat activation, hematopoietic homeostasis, and innate immunity in c-fes-/- mice. Immunity. 2000;13:397–407
  134. Graves PE, Kabesch M, Halonen M, Holberg CJ, Baldini M, Fritzsch C, et al.  A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children. J Allergy Clin Immunol. 2000;105:506–513
  135. van der Pouw Kraan TC, van Veen A, Boeije LC, van Tuyl SA, de Groot ER, Stapel SO, et al.  An IL-13 promoter polymorphism associated with increased risk of allergic asthma. Genes Immun. 1999;1:61–65
  136. Heinzmann A, Mao XQ, Akaiwa M, Kreomer RT, Gao PS, Ohshima K, et al.  Genetic variants of IL-13 signalling and human asthma and atopy. Hum Mol Genet. 2000;9:549–559
  137. Liu X, Nickel R, Beyer K, Wahn U, Ehrlich E, Friedhoff LR, et al.  An IL13 coding region variant is associated with a high total serum IgE level and atopic dermatitis in the German multicenter atopy study (MAS-90). J Allergy Clin Immunol. 2000;106:167–170
  138. Arima K, Umeshita-Suyama R, Sakata Y, Akaiwa M, Mao XQ, Enomoto T, et al.  Upregulation of IL-13 concentration in vivo by the IL13 variant associated with bronchial asthma. J Allergy Clin Immunol. 2002;109:980–987
  139. Deichmann KA, Heinzmann A, Forster J, Dischinger S, Mehl C, Brueggenolte E, et al.  Linkage and allelic association of atopy and markers flanking the IL4-receptor gene. Clin Exp Allergy. 1998;28:151–155
  140. Deichmann K, Bardutsky J, Forster J, Heinzmann A, Kuehr J. Common polymorphisms in the coding part of the IL4-receptor gene. Biochim Biophys Acta. 1997;231:696–697
  141. Kruse S, Japha T, Tedner M, Sparholt SR, Forster J, Kuehr J, et al.  The polymorphisms S503P and Q576R in the interleukin-4 receptor alpha gene are associated with atopy and influence the signal transduction. Immunology. 1999;96:365–371
  142. Ober C, Leavitt SA, Tsalenko A, Howard TD, Hoki DM, Daniel R, et al.  Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations. Am J Hum Genet. 2000;66:517–526
  143. Mitsuyasu H, Izuhara K, Mao XQ, Gao PS, Arinobu Y, Enomoto T, et al.  Ile50Val variant of IL4R alpha upregulates IgE synthesis and associates with atopic asthma. Nat Genet. 1998;19:119–120
  144. Rosa-Rosa L, Zimmermann N, Bernstein JA, Rothenberg ME, Khurana Hershey GK. The R576 IL-4 receptor alpha allele correlates with asthma severity. J Allergy Clin Immunol. 1999;104:1008–1014
  145. Risma KA, Wang N, Andrews RP, Cunningham CM, Ericksen MB, Bernstein JA, et al.  V75R576 IL-4 receptor alpha is associated with allergic asthma and enhanced IL-4 receptor function. J Immunol. 2002;169:1604–1610
  146. Howard TD, Koppelman GH, Xu J, Zheng SL, Postma DS, Meyers DA, et al.  Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma. Am J Hum Genet. 2002;70:230–236
  147. Katagiri K, Itami S, Hatano Y, Takayasu S. Increased levels of IL-13 mRNA, but not IL-4 mRNA, are found in vivo in peripheral blood mononuclear cells (PBMC) of patients with atopic dermatitis (AD). Clin Exp Immunol. 1997;108:289–294
  148. Akdis M, Akdis CA, Weigl L, Disch R, Blaser K. Skin-homing, CLA+ memory T cells are activated in atopic dermatitis and regulate IgE by an IL-13-dominated cytokine pattern: IgG4 counter-regulation by CLA- memory T cells. J Immunol. 1997;159:4611–4619
  149. Pawankar RU, Okuda M, Hasegawa S, Suzuki K, Yssel H, Okubu K, et al.  Interleukin-13 expression in the nasal mucosa of perennial allergic rhinitis. Am J Respir Crit Care Med. 1995;152:2059–2067
  150. Prieto J, Lensmar C, Roquet A, van der Ploeg I, Gigliotti D, Eklund A, et al.  Increased interleukin-13 mRNA expression in bronchoalveolar lavage cells of atopic patients with mild asthma after repeated low-dose allergen provocations. Respir Med. 2000;94:806–814
  151. Huang SK, Xiao HQ, Kleine-Tebbe J, Paciotti G, Marsh DG, Lichtenstein LM, et al.  IL-13 expression at the sites of allergen challenge in patients with asthma. J Immunol. 1995;155:2688–2694
  152. Humbert M, Durham SR, Kimmitt P, Powell N, Assoufi B, Pfister R, et al.  Elevated expression of messenger ribonucleic acid encoding IL-13 in the bronchial mucosa of atopic and nonatopic subjects with asthma. J Allergy Clin Immunol. 1997;99:657–665
  153. Bodey KJ, Semper AE, Redington AE, Madden J, Teran LM, Holgate ST, et al.  Cytokine profiles of BAL T cells and T-cell clones obtained from human asthmatic airways after local allergen challenge. Allergy. 1999;54:1083–1093
  154. Obiri NI, Debinski W, Leonard WJ, Puri RK. Receptor for interleukin 13. Interaction with interleukin 4 by a mechanism that does not involve the common gamma chain shared by receptors for interleukins 2, 4, 7, 9, and 15. J Biol Chem. 1995;270:8797–8804
  155. Puri RK, Leland P, Obiri NI, Husain SR, Kreitman RJ, Haas GP, et al.  Targeting of interleukin-13 receptor on human renal cell carcinoma cells by a recombinant chimeric protein composed of interleukin-13 and a truncated form of Pseudomonas exotoxin A (PE38QQR). Blood. 1996;87:4333–4339
  156. Kapp U, Yeh WC, Patterson B, Elia AJ, Kagi D, Ho A, et al.  Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells. J Exp Med. 1999;189:1939–1946

☆ Supported in part by National Institutes of Health grant no. R01AI46652-01A1.

☆☆ Reprint requests: Gurjit K. Khurana Hershey, MD, PhD, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati OH 45229.

★ This activity is available for CME credit. See page 41A for important information.

PII: S0091-6749(03)00697-3

doi:10.1067/mai.2003.1333

The Journal of Allergy and Clinical Immunology
Volume 111, Issue 4 , Pages 677-690, April 2003

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