HGNC Approved Gene Symbol: IL13
Cytogenetic location: 5q31.1 Genomic coordinates (GRCh38) : 5:132,656,522-132,661,110 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.1 | {Allergic rhinitis, susceptibility to} | 607154 | 3 | |
| {Asthma, susceptibility to} | 600807 | Autosomal dominant | 3 |
By differential screening of an organized subtracted cDNA library from activated peripheral blood mononuclear cells, using the inducibility of lymphokine mRNAs by anti-CD28 as a primary screening criterion, Minty et al. (1993) discovered a new lymphokine, interleukin-13, which is expressed in activated human T lymphocytes. Recombinant IL13 protein inhibits inflammatory cytokine production induced by lipopolysaccharide in human peripheral blood monocytes. Moreover, it synergizes with IL2 (147680) in regulating interferon-gamma synthesis in large granular lymphocytes. Minty et al. (1993) suggested that interleukin-13 may be critical in regulating inflammatory and immune responses. McKenzie et al. (1993) also isolated a cDNA for interleukin-13 and showed that the IL13 protein has a relative molecular mass of about 10,000.
Punnonen et al. (1993) demonstrated that IL13 induces IgG4 and IgE synthesis by human B cells. The activity of IL13 was shown to be independent of IL4 (147780), but these 2 cytokines may have common signaling pathways. Like IL4, IL13 induced CD23 expression on B cells, enhanced CD72, surface IgM, and class II MHC antigen expression, and induced germline IgE heavy-chain gene transcription in highly purified B cells. Zurawski and de Vries (1994) reviewed the differences and similarities in the actions of IL13 and IL4 and the differences in IL13 in human and mouse cells.
Because IL4 and IL13 and their specific signaling pathways are considered attractive targets for the treatment of allergy and asthma, Kelly-Welch et al. (2003) reviewed the signaling connections of these cytokines. IL4 interacts with IL4R (147781) with high affinity, leading to dimerization with either the common gamma chain (IL2RG; 308380), a component of receptors for a number of cytokines, to create a type I receptor, or with IL13RA1 (300119) to form a type II receptor. IL13, on the other hand, binds with high affinity to IL13RA1, which induces heterodimerization with IL4R to form a complex identical to the type II receptor. Alternatively, IL13 may bind with even greater affinity to IL13RA2 (300130), which fails to induce a signal, indicating that it acts as a decoy receptor. The C-terminal tails of the IL4 and IL13 receptor subunits interact with tyrosine kinases of the Janus kinase family (e.g., JAK1; 147795), leading to interaction with STAT6 (601512), which binds to consensus sequences in the promoters of IL4- and IL13-regulated genes. Kelly-Welch et al. (2003) proposed that subtle differences in IL4 and IL13 signaling due to polymorphisms near docking sites in IL4R may have profound implications for allergy and asthma.
Zhu et al. (2004) demonstrated that acidic mammalian chitinase (AMCase; 606080) is induced via a T helper-2 (Th2)-specific, IL13-mediated pathway in epithelial cells and macrophages in an aeroallergen asthma model in mice and expressed in exaggerated quantities in human asthma. AMCase neutralization ameliorated Th2 inflammation and airway hyperresponsiveness in mice, in part by inhibiting IL13 pathway activation and chemokine induction. Zhu et al. (2004) concluded that AMCase may be an important mediator of IL13-induced responses in Th2-dominated disorders such as asthma. They found that expression of AMCase was not readily apparent in human lung samples derived from control patients with nonpulmonary disease, but was readily detected in epithelial cells and macrophages in tissue samples taken from patients with asthma. In these studies, the percentage of the epithelium with AMCase mRNA expression and the number of AMCase-positive subepithelial cells in samples from asthmatics were significantly greater than seen in controls. Zhu et al. (2004) also found that AMCase contributes downstream during IL13-induced pathology.
Type 2 immunity, which is responsible for protective immune responses to helminth parasites and is the underlying cause of the pathogenesis of allergic asthma, consists of responses dominated by the cardinal type 2 cytokines IL4, IL5 (147850), and IL13. T cells are an important source of these cytokines in adaptive immune responses, but the innate cell sources remained to be comprehensively determined. Using Il13-eGFP reporter mice, Neill et al. (2010) identified and functionally characterized a novel innate type 2 immune effector leukocyte that they called the nuocyte. Nuocytes expand in vivo in response to the type 2-inducing cytokines IL25 (605658) and IL33 (608678), and represent the predominant early source of IL13 during helminth infection with Nippostrongylus brasiliensis. In the combined absence of IL25 and IL33 signaling, nuocytes failed to expand, resulting in a severe defect in worm expulsion that was rescued by the adoptive transfer of in vitro cultured wildtype, but not Il13-deficient, nuocytes. Thus, Neill et al. (2010) concluded that nuocytes represent a critically important innate effector cell in type 2 immunity.
Wu et al. (2011) showed that eosinophils are the major IL4-expressing cells in white adipose tissues of mice and, in their absence, alternatively activated macrophages are greatly attenuated. Eosinophils migrate into adipose tissue by an integrin-dependent process and reconstitute alternatively activated macrophages through an IL4- or IL13-dependent process. Mice fed a high-fat diet developed increased body fat, impaired glucose tolerance, and insulin resistance in the absence of eosinophils, and helminth-induced adipose tissue eosinophilia enhanced glucose tolerance. Wu et al. (2011) concluded that eosinophils may play an unexpected role in metabolic homeostasis through maintenance of adipose alternatively activated macrophages.
Nussbaum et al. (2013) showed that serum IL5 levels are maintained by long-lived type 2 innate lymphoid (ILC2) cells resident in peripheral tissues. ILC2 cells secrete IL5 constitutively and are induced to coexpress IL13 during type 2 inflammation, resulting in localized eotaxin production and eosinophil accumulation. In the small intestine where eosinophils and eotaxin (see 601156) are constitutive, ILC2 cells coexpress IL5 and IL13; this coexpression is enhanced after caloric intake. The circadian synchronizer vasoactive intestinal peptide (VIP; 192320) also stimulates ILC2 cells through the VPAC2 receptor (VIPR2; 601970) to release IL5, linking eosinophil levels with metabolic cycling. Tissue ILC2 cells regulate basal eosinophilopoiesis and tissue eosinophil accumulation through constitutive and stimulated cytokine expression, and this dissociated regulation can be tuned by nutrient intake and central circadian rhythms.
Bosurgi et al. (2017) showed that IL4 (147780) or IL13 alone was not sufficient, but IL4 or IL13 together with apoptotic cells, induced the tissue repair program in macrophages. Genetic ablation of sensors of apoptotic cells impaired the proliferation of tissue-resident macrophages and the induction of antiinflammatory and tissue repair genes in the lungs after helminth infection or in the gut after induction of colitis. By contrast, the recognition of apoptotic cells was dispensable for cytokine-dependent induction of pattern recognition receptor (CLEC7A; 606264), cell adhesion, or chemotaxis genes in macrophages. Detection of apoptotic cells can therefore spatially compartmentalize or prevent premature or ectopic activity of pleiotropic, soluble cytokines such as IL4 or IL13.
Knudsen et al. (2020) found that the type 2 cytokine IL13 is induced in exercising muscle, where it orchestrates metabolic reprogramming that preserves glycogen in favor of fatty acid oxidation and mitochondrial respiration. Exercise training-mediated mitochondrial biogenesis, running endurance, and beneficial glycemic effects were lost in Il13-null mice. By contrast, enhanced muscle IL13 signaling was sufficient to increase running distance, glucose tolerance, and mitochondrial activity similar to the effects of exercise training. In muscle, IL13 acts through both its receptor IL13R-alpha-1 (300119) and the transcription factor Stat3 (102582). The genetic ablation of either of these downstream effectors reduced running capacity in mice. Thus, Knudsen et al. (2020) concluded that coordinated immunologic and physiologic responses mediate exercise-elicited metabolic adaptations that maximize muscle fuel economy.
LaPorte et al. (2008) reported the crystal structures of the complete set of IL4 and IL13 type I (IL4RA/IL2RG/IL4) and type II (IL4RA/IL13RA1/IL4 and IL4RA/IL13RA1/IL13) ternary signaling complexes at the 3.0-angstrom level. They noted that the type I receptor complex is more active in regulating Th2 development, whereas the type II receptor complex is not found on T cells and is more active in regulating cells that mediate airway hypersensitivity and mucus secretion. The type I complex revealed a structural basis for the ability of IL2RG to recognize 6 different IL2RG cytokines.
The structure of the gene for interleukin-13 is closely similar to that of IL3 (147740), IL5, IL4, and GMCSF (CSF2; 138960).
The IL13 gene is clustered with IL3, IL5, IL4, and CSF2 on 5q (Morgan et al., 1992). Physical maps of the 5q23-q31 region show the following order: cen--IL3--CSF2--IL13--IL4--IL5--tel, with IL13 particularly close to IL4 (Paul, 1993).
Smirnov et al. (1995) showed that the IL13 gene is located 12 kb upstream of the IL4 gene in a tail-to-head orientation and discussed the similarities in organization between the 2 genes.
Heinzmann et al. (2000) determined that the R130Q variant of IL13 (147683.0002), which they referred to as R110Q, associated with asthma in case-control populations from Britain and Japan (peak odds ratio (OR) = 2.31, 95% confidence interval, 1.33 - 4.00); the variant also predicted asthma and higher serum IL13 levels in a general, Japanese pediatric population. Chen et al. (2004) noted that R110Q numbering does not include a 20-amino acid signal sequence and that the R110Q variant has been referred to as R130Q. Immunohistochemistry demonstrated that both subunits of IL13R are prominently expressed in bronchial epithelium and smooth muscle from asthmatic subjects. Detailed molecular modeling analyses indicated that residue 110 of IL13 is important in the internal constitution of the ligand and crucial in ligand-receptor interaction.
To investigate whether IL13 gene polymorphisms are associated with the development of Graves disease (GD; 275000), Hiromatsu et al. (2005) studied IL13 gene polymorphisms in 310 Japanese GD patients and 244 healthy control subjects without antithyroid autoantibodies or a family history of autoimmune disorders. They found a significant decrease in frequency of the -1112T allele (147683.0001) in GD patients compared with controls (16% vs 23%; P = 0.0019). The frequency of the 2044A allele on exon 4 (147683.0002) also appeared lower in GD patients compared with controls. Haplotype analysis showed a significant decrease in the -1112T/2044A haplotype in GD patients.
Long-range regulatory elements are difficult to discover experimentally; however, they tend to be conserved among mammals, suggesting that cross-species sequence comparisons should identify them. To search for regulatory sequences, Loots et al. (2000) examined about 1 megabase of orthologous human and mouse sequences for conserved noncoding elements with greater than or equal to 70% identity over at least 100 basepairs. Ninety noncoding sequences meeting these criteria were discovered, and the analysis of 15 of these elements found that about 70% were conserved across mammals. Characterization of the largest element in transgenic mice propagating human 5q31 yeast artificial chromosomes revealed it to be a coordinate regulator of 3 genes, interleukin-4, interleukin-13, and interleukin-5. This conserved noncoding sequence, called CNS1 by Loots et al. (2000), is 401 bp long and is located in the intergenic region, approximately 13 kb, between IL4 and IL13. CNS1 demonstrates a high degree of conservation across mammals (80% identity in mice, humans, cows, dogs, and rabbits), which contrasts sharply with the relatively low conservation observed in the coding regions of the flanking genes, IL4 and IL13, which have only 50% identity between humans and mice. This element is single copy in the human genome and has been conserved during evolution, not only with regards to sequence but also to genomic location, having been mapped in dogs, baboons, humans, and mice to the IL4-IL13 intergenic region. Experiments in transgenic mice revealed that CNS1 acts through its effect on the transcriptional activity of IL4, IL13, and IL5. Expression of other genes in the YAC had no change relative to wildtype in activated Th2 cells or other tissues tested.
The pathogenesis of asthma involves, in part, activity of T-cell cytokines. Murine models support participation of IL4 and IL4R in asthma. Grunig et al. (1998) found that selective neutralization of Il13, which, like Il4, binds to the alpha-chain of the Il4 receptor, ameliorated the asthma phenotype, including airway hyperresponsiveness, eosinophil recruitment, and mucus overproduction. Administration of either Il13 or Il4 conferred an asthma-like phenotype to nonimmunized T cell-deficient mice by an Il4 receptor alpha-chain-dependent pathway.
In mice, Wills-Karp et al. (1998) found that Il13 is necessary and sufficient for the expression of allergic asthma. Il13 induced the pathophysiologic features of asthma in a manner that was independent of immunoglobulin E and eosinophils. Thus, Wills-Karp et al. (1998) concluded that IL13 is critical to allergen-induced asthma but operates through mechanisms other than those that are classically implicated in allergic responses although IL4 may be of immunoregulatory importance, it appears not to be a prime effector molecule.
In transgenic mice, Zhu et al. (1999) produced targeted pulmonary expression of Il13 and found that it causes a mononuclear and eosinophilic inflammatory response, mucus cell metaplasia, deposition of Charcot-Leyden-like crystals, airway fibrosis, production of eotaxin, airways obstruction, and nonspecific airways hyperresponsiveness. They suggested that IL13 may play an important role in the pathogenesis of similar responses in asthma.
By analysis of human YAC transgenic mice containing the 5q31 cytokine genes, Lacy et al. (2000) determined that the human proteins are produced under Th2 conditions in vitro and in response to Nippostrongylus brasiliensis, a Th2-inducing stimulus, in vivo. The authors observed no adverse effects on murine lymphoid organs. Fewer cells produced the endogenous mouse cytokines in transgenic than in control mice, suggesting competition for stable expression between the mouse and human genes. The data also suggested that regulatory elements within the human transgene are capable of interacting with trans-acting murine factors.
Zheng et al. (2000) targeted inducible IL13 to the lung in transgenic mice and showed that this cytokine, when inducibly overexpressed, causes emphysema with enhanced lung volumes and compliance, mucus metaplasia, and inflammation. Matrix metalloproteinases (MMPs) and cathepsins were induced by IL13 in the lungs of these mice. In addition, treatment with MMP or cysteine proteinase antagonists significantly decreased the emphysema and inflammation, but not the mucus, in these animals. The experiments demonstrated that IL13 causes emphysema via MMP- and cathepsin-dependent pathways and highlighted common mechanisms that may underlie chronic obstructive pulmonary disease (COPD; 606963) and asthma.
Kuperman et al. (2002) showed that mice lacking STAT6 were protected from all pulmonary effects of IL13. Reconstitution of STAT6 only in epithelial cells was sufficient for IL13-induced airway hyperreactivity and mucus production in the absence of inflammation, fibrosis, or other lung pathology. These results demonstrated the importance of direct effects of IL13 on epithelial cells in causing 2 central features of asthma.
By examining the effects of an Il13 transgene on wildtype mice and mice lacking Mmp9 (120361) or Mmp12 (601046), Lanone et al. (2002) determined that the IL13-mediated eosinophilic and lymphocytic inflammation and alveolar remodeling in the lung that occurs in asthma (600807), COPD, and interstitial lung disease is dependent on both MMP9 and MMP12 mechanisms. The results indicated that MMP9 inhibits neutrophil accumulation, but, unlike MMP12, has no effect on eosinophil, macrophage, or lymphocyte accumulation. Furthermore, IL13-induced production of MMP2 (120360), MMP9, MMP13 (600108), and MMP14 (600754) was found to be dependent on MMP12.
In mice overexpressing Il13 in the lung, Blackburn et al. (2003) observed pulmonary inflammation and remodeling accompanied by a progressive increase in adenosine accumulation, inhibition of adenosine deaminase (ADA; 608958) activity and mRNA accumulation, and increased expression of several adenosine receptors (see 102776). Ada enzyme therapy diminished the Il13-induced increase in adenosine, inhibited Il13-induced inflammation, chemokine elaboration, fibrosis, and alveolar destruction, and prolonged the survival of IL13 transgenic mice. Il13 was strongly induced by adenosine in Ada null mice. Blackburn et al. (2003) concluded that adenosine and adenosine signaling contribute to and influence the severity of IL13-induced tissue responses and that IL13 and adenosine stimulate one another in an amplification pathway.
Chen et al. (2005) found that transgenic mice overexpressing Il13 specifically in lung showed upregulation of both Il11 (147681) and Il11ra (600939), but not Il6r (147880), as well as upregulation of other IL6 (147620)-type cytokines and a modest increase in gp130 (IL6ST; 600694). Il13 transgenic Il11ra -/- mice exhibited a decrease in the inflammatory response seen in Il13 transgenic Il13ra +/+ mice, as well as reduced fibrosis, hyaluronic acid accumulation, chemokine production, and alveolar remodeling response. Il13 transgenic Il11ra -/- mice also survived significantly longer than Il13 transgenic Il11ra +/+ mice. Chen et al. (2005) concluded that IL11RA plays a key role in the pathogenesis of IL13-induced inflammation and remodeling. They proposed that IL11, which is induced simultaneously with IL13 in inflammatory disorders such as asthma, may mediate the tissue effects of IL13.
IL13 is a major inducer of fibrosis in many chronic infectious and autoimmune diseases. In studies of the mechanisms underlying such induction in mice, Fichtner-Feigl et al. (2006) found that IL13 induced transforming growth factor-beta-1 (TGFB1; 190180) in macrophages through a 2-stage process involving, first, the induction of a receptor formerly considered to function only as a decoy receptor, IL13R-alpha-2 (IL13RA2; 300130). Such induction required IL13 (or IL4) and tumor necrosis factor-alpha (TNFA; 191160). In vivo, they found that prevention of IL13RA2 expression reduced production of TGFB1 in oxazolone-induced colitis and that prevention of IL13RA2 expression, IL13RA2 gene silencing, or blockade of IL13RA2 signaling led to marked downregulation of TGFB1 production and collagen deposition in bleomycin-induced lung fibrosis. These data suggested that IL13RA2 signaling during prolonged inflammation is an important therapeutic target for the prevention of TGFB1-mediated fibrosis.
Howard et al. (2001) reported that the -1112C-T promoter variant, which they referred to as -1111C-T, of the IL13 gene contributes significantly to bronchial hyperresponsiveness and asthma susceptibility (600807) but not to total serum IgE levels. In studies of Dutch families ascertained through a proband with asthma, Howard et al. (2002) found significant associations of atopy and asthma-related phenotypes with several IL4R (147781) polymorphisms, including S503P (147781.0003), and total serum IgE levels. A significant gene-gene interaction between S503P in IL4RA and the -1111 promoter variation in IL13 was detected. Individuals with the risk genotype for both genes were at almost 5 times greater risk for the development of asthma compared to individuals with both nonrisk genotypes. The data suggested that variations in IL4R contribute to elevated total serum IgE levels and that interaction between IL4R and IL13 markedly increases an individual's susceptibility to asthma.
He et al. (2003) noted that this polymorphism is referred to as -1112C-T relative to the transcription start site, but it has also been referred to as -1055C-T and -1111C-T.
Infection with cercaria of the trematode parasite, Schistosoma hematobium, results in male/female worm pairs inhabiting the vesical venous plexus and producing 300 to 3,000 eggs daily. These eggs may lodge in bladder and ureter walls, causing sometimes fatal obstructive nephropathy. Other eggs pass through blood-tinged urine and may infect host aquatic snails, which eventually shed infectious cercaria. Resistance to infection, but not disease, is associated with Th2 immunity. Susceptibility to Schistosoma infection is controlled by a locus that includes IL4, IL5, and IL13 (see 181460). Kouriba et al. (2005) evaluated polymorphisms in these genes in families in 2 Dogon villages in Mali where S. hematobium infection is endemic. They identified 2 SNPs in the IL13 promoter, -1055C/T and -591A/G, and found that the -1055C and -591A alleles were significantly transmitted to children with the highest infectious burden, as measured by urinary egg counts and serum worm antigen levels. Protection against S. hematobiuma infection was associated with the -1055TT genotype, which Kouriba et al. (2005) noted also aggravates asthma.
Heinzmann et al. (2000) determined that R130Q variant of IL13, which they referred to as R110Q, associated with asthma in case-control populations from Britain and Japan (peak odds ratio (OR) = 2.31, 95% confidence interval, 1.33 - 4.00); the variant also predicted asthma and higher serum IL13 levels in a general, Japanese pediatric population. Chen et al. (2004) noted that R110Q numbering does not include a 20-amino acid signal sequence and that the R110Q variant has been referred to as R130Q. Immunohistochemistry demonstrated that both subunits of IL13R are prominently expressed in bronchial epithelium and smooth muscle from asthmatic subjects. Detailed molecular modeling analyses indicated that residue 110 of IL13 is important in the internal constitution of the ligand and crucial in ligand-receptor interaction.
In Chinese adult patients with allergic rhinitis (607154), Wang et al. (2003) found a significant association of the IL13 arg130-to-gln (R130Q) SNP, but not of the IL13 promoter -1112C-T SNP (147683.0001), with serum total IgE levels. Patients with a gln/gln genotype showed much higher serum total IgE than those with an arg/arg genotype.
Hiromatsu et al. (2005) noted that the R130Q amino acid substitution arises from a G-to-A transition at nucleotide 2044 (G2044A) in exon 4 of the IL13 gene.
Vladich et al. (2005) examined the impact of the IL13 R130Q variant on the functional properties of IL13 by comparing the activity of the variant to wildtype IL13 on primary effector cells of human allergic inflammation. IL13 R130Q was significantly more active than wildtype IL13 in multiple effector assays and was neutralized less effectively by an IL13R-alpha-2 decoy. Vladich et al. (2005) suggested that natural variation in the coding region of IL13 may be an important genetic determinant of susceptibility to allergy.
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