Interleukin 13

Last updated
IL13
Protein IL13 PDB 1ga3.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases IL13 , IL-13, P600, interleukin 13
External IDs OMIM: 147683 MGI: 96541 HomoloGene: 1649 GeneCards: IL13
Orthologs
SpeciesHumanMouse
Entrez

3596

16163

Ensembl

ENSG00000169194

ENSMUSG00000020383

UniProt

P35225

P20109

RefSeq (mRNA)

NM_002188

NM_008355

RefSeq (protein)

NP_002179
NP_001341920
NP_001341921
NP_001341922

NP_032381

Location (UCSC)n/a Chr 11: 53.52 – 53.53 Mb
PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

Interleukin 13 (IL-13) is a protein that in humans is encoded by the IL13 gene. [4] [5] [6] IL-13 was first cloned in 1993 and is located on chromosome 5q31.1 with a length of 1.4kb. [4] It has a mass of 13 kDa and folds into 4 alpha helical bundles. [7] The secondary structural features of IL-13 are similar to that of Interleukin 4 (IL-4); however it only has 25% sequence identity to IL-4 and is capable of IL-4 independent signaling. [7] [4] [8] IL-13 is a cytokine secreted by T helper type 2 (Th2) cells, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils and nuocytes. [7] Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation. [7] It is a mediator of allergic inflammation and different diseases including asthma. [7]

Functions

IL-13 has effects on immune cells that are similar to those of the closely related cytokine IL-4. [4] However, IL-13 is suspected to be the central mediator of the physiologic changes induced by allergic inflammation in many tissues. [4]

Although IL-13 is associated primarily with the induction of airway disease, it also has anti-inflammatory properties. [4] IL-13 induces a class of protein-degrading enzymes, known as matrix metalloproteinases (MMPs), in the airways. [4] These enzymes are required to induce aggression of parenchymal inflammatory cells into the airway lumen, where they are then cleared. [4] Among other factors, IL-13 induces these MMPs as part of a mechanism that protects against excessive allergic inflammation that predisposes to asphyxiation. [4]

IL-13 is known to induce changes in hematopoietic cells, but these effects are probably less important than that of IL-4. [4] Furthermore, IL-13 can induce immunoglobulin E (IgE) secretion from activated human B cells. [4] [7] Deletion of IL-13 from mice does not markedly affect either Th2 cell development or antigen-specific IgE responses induced by potent allergens. [4] In comparison, deletion of IL-4 deactivates these responses. Thus, rather than a lymphoid cytokine, IL-13 acts more prominently as a molecular bridge linking allergic inflammatory cell to the non-immune cells in contact with them, thereby altering physiological function. [4]

The signaling of IL-13 begins through a shared multi-subunit receptor with IL-4. [7] This receptor is a heterodimer receptor complex consisting of alpha IL-4 receptor (IL-4Rα) and alpha Interleukin-13 receptor (IL-13R1). [7] The high affinity of IL-13 to the IL-13R1 leads to their bond formation which further increase the probability of a heterodimer formation to IL-4R1 and the production of the type 2 IL-4 receptor. Heterodimerization activates both the STAT6 and the IRS. [7] STAT6 signaling is important in initiation of the allergic response. [7] Most of the biological effects of IL-13, like those of IL-4, are linked to a single transcription factor, signal transducer and activator of transcription 6 (STAT6). [7] Interleukin-13 and its associated receptors with α subunit of the IL-4 receptor (IL-4Rα) allows for the downstream activation of STAT6. [9] The JAK Janus kinase proteins on the cytoplasmic end of the receptors allows for the phosphorylation of STAT6, which then forms an activated homodimer and are transported to the nucleus. [9] Once, in the nucleus, STAT6 heterodimer molecule regulates gene expression of cell types critical to the balance between host immune defense and allergic inflammatory responses such as the development of Th2. [9] This can be resulted from an allergic reaction brought about when facing an Ala gene. IL-13 also binds to another receptor known as IL-13Rα2. [10] IL-13Rα2 (which is labelled as a decoy receptor) is derived from Th2 cells and is a pleotropic immune regulatory cytokine. [10] IL-13 has greater affinity (50-times) to IL-13Rα2 than to IL-13Ra1. [10] The IL-13Rα2 subunit binds only to IL-13 and it exists in both membrane-bound and soluble forms in mice. [10] A soluble form of IL-13Rα2 has not been detected in human subjects. [10] Studies of IL-13 transgenic mice lungs with IL-13Rα2 null loci indicated that IL-13Rα2 deficiency significantly augmented IL-13 or ovalbumin-induced pulmonary inflammation and remodeling. [10] Most normal cells, such as immune cells or endothelial cells, express very low or undetectable levels of IL-13 receptors. [10] Research has shown that cell-surface expression of IL-13Rα2 on human asthmatic airway fibroblasts was reduced compared with expression on normal control airway fibroblasts. [10] This supported the hypothesis that IL-13Rα2 is a negative regulator of IL-13–induced response and illustrated significantly reduced production of TGF-β1 and deposition of collagen in the lungs of mice. [10]

Interleukin-13 has a critical role in goblet cell metaplasia. [11] Goblet cells are filled with mucin (MUC). [11] MUC5AC Mucin 5AC is a gel-like mucin product of goblet cells. [11] Interleukin-13 induces goblet cell differentiation and allows for the production of MUC5AC in tracheal epithelium. [11] 15-Lipoxygenase-1 (15LO1) which is an enzyme in the fatty acid metabolism and its metabolite, 15-HETE, are highly expressed in asthma (which lead to the overexpression of MUC5AC) and are induced by IL-13 in human airway epithelial cells. With the increasing number of goblet cells, there is the production of excessive mucus within the bronchi. [11] The functional consequences of the changes in MUC storation and secretion contributes to the pathophysiologic mechanisms for various clinical abnormalities in asthmatic patients including sputum production, airway narrowing, exacerbation and accelerated loss in lung function. [11]

Additionally, IL-13 has been shown to induce a potent fibrogenic program during the course of diverse diseases marked by elevated Type 2 cytokines such as chronic schistosomiasis and atopic dermatitis among others. It has been suggested that this fibrogenic program is critically dependent on direct IL-13 signaling through IL-4Rα on PDGFRβ+ fibroblasts. [12]

Evolution

IL-13 is closely related to IL-4, and both stimulate Type 2 immunity. [13] Genes of this family have also been found in fish, both in bony fish [14] [15] and cartilaginous fish; [16] because at that evolutionary level they can't be distinguished as IL-4 or IL-13, they have been named IL-4/13. [15]

Clinical significance

IL-13 specifically induces physiological changes in parasitized organs that are required to expel the offending organisms or their products. For example, expulsion from the gut of a variety of mouse helminths requires IL-13 secreted by Th2 cells. IL-13 induces several changes in the gut that create an environment hostile to the parasite, including enhanced contractions and glycoprotein hyper-secretion from gut epithelial cells, that ultimately lead to detachment of the organism from the gut wall and their removal. [17]

The eggs of the parasite Schistosoma mansoni may lodge in a variety of organs including the gut wall, liver, lung and even central nervous system, inducing the formation of granulomas under the control of IL-13. Here, however, the eventual result is organ damage and often profound or even fatal disease, not resolution of the infection. An emerging concept is that IL-13 may antagonize Th1 responses that are required to resolve intracellular infections. In this immune dysregulated context, marked by the recruitment of aberrantly large numbers of Th2 cells, IL-13 inhibits the ability of host immune cells to destroy intracellular pathogens.

IL-13 expression has demonstrated to be increased in bronchoalveolar lavage (BAL) fluid and cells in patients with atopic mild asthma after allergen challenge. [18] Genome-wide association studies have identified multiple polymorphisms of IL-13 and genes encoding the IL-13 receptors as associated with asthma susceptibility, bronchial hyperresponsiveness, and increased IgE levels. [18] The overexpression of IL-13 induces many features of allergic lung disease, including airway hyperresponsiveness, goblet cell metaplasia, mucus hypersecretion and airway remodelling which all contribute to airway obstruction. [19] murine studies demonstrated that IL-13 was both necessary and sufficient to generate asthma-like Th2 responses in the mouse lung. [7] IL-13 is mainly overexpressed in sputum, bronchial submucosa, peripheral blood and mast cells in the airway smooth muscle bundle. [7] IL-4 contributes to these physiologic changes, but is less important than IL-13. IL-13 also induces secretion of chemokines that are required for recruitment of allergic effector cells to the lung. Studies of STAT6 transgenic mice suggest the possibility that IL-13 signaling occurring only through the airway epithelium is required for most of these effects. While no studies have yet directly implicated IL-13 in the control of human diseases, many polymorphisms in the IL-13 gene have been shown to confer an enhanced risk of atopic respiratory diseases such as asthma. [17] In a study conducted with knockout mice model for asthma, air resistance, mucus production and profibrogenic mediator induction were solely found to be dependent on the presence of IL-13R1 and not IL-13Rα2. [7] Studies on transgenic mouse in vivo demonstrate that lung over-expression of IL-13 induces subepithelial airway fibrosis. [7] IL-13 is the dominant effector in toxin, infection, allergic, and post-transplant bronchiolitis obliterans models of fibrosis. [7]

Other research suggests that IL-13 is responsible for the promotion of the survival and the migration of epithelial cells, production of inducible nitric oxide synthase by airway epithelial cells, activation of macrophages, permeability of the epithelial cells, and transformation of airway fibroblasts to myofibroblasts leading to collagen deposition. [18] The deposition then influences the airway remodelling in asthmatic patients. [18]

Besides its well-established role in respiratory diseases IL-13 also plays a role in anti-inflammatory processes of other organs. It suppresses proinflammatory mediators and it is involved in wound repair after injury. [20] In type I diabetes, IL-13 antagonized cytotoxic insults to pancreatic β cells enhanced by IL-6. [21] In a mouse model of acetaminophen-induced liver injury eosinophil-driven IL-4/IL-13 mediated hepatoprotective function. [22] In severe alcohol-associated hepatitis low plasma level of IL-13 is a predictor of short-term (90-day) mortality. [23] However, in contrast to its short-term beneficiary effects in acute situations, chronically increased IL-13 contributes to development of fibrosis and cirrhosis. [24]

Dupilumab is a monoclonal antibody IL-13 and IL-4 modulator that targets the shared receptor of IL-4 and IL-13, IL4Rα. [25] Since IL-4 and IL-13 have similar biological activities, dupilumab may be an effective form of treatment for asthmatic patients. [25] Cendakimab is also a monoclonal antibody to the IL-13 receptor. [26]

See also

Related Research Articles

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Eosinophil</span> Variety of white blood cells

Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma. They are granulocytes that develop during hematopoiesis in the bone marrow before migrating into blood, after which they are terminally differentiated and do not multiply.

<span class="mw-page-title-main">Goblet cell</span> Epithelial cells that secrete mucins

Goblet cells are simple columnar epithelial cells that secrete gel-forming mucins, like mucin 5AC. The goblet cells mainly use the merocrine method of secretion, secreting vesicles into a duct, but may use apocrine methods, budding off their secretions, when under stress. The term goblet refers to the cell's goblet-like shape. The apical portion is shaped like a cup, as it is distended by abundant mucus laden granules; its basal portion lacks these granules and is shaped like a stem.

<span class="mw-page-title-main">Interleukin 4</span> Mammalian protein found in Mus musculus

The interleukin 4 is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, Th2 cells, eosinophils and basophils. It is closely related and has functions similar to IL-13.

Interleukin 5 (IL-5) is an interleukin produced by type-2 T helper cells and mast cells.

<span class="mw-page-title-main">Interleukin 33</span> IL-33 induces helper T cells, mast cells, eosinophils and basophils to produce type 2 cytokines.

Interleukin 33 (IL-33) is a protein that in humans is encoded by the IL33 gene.

<span class="mw-page-title-main">Interleukin 31</span>

Interleukin-31 (IL-31) is a protein that in humans is encoded by the IL31 gene that resides on chromosome 12. IL-31 is an inflammatory cytokine that helps trigger cell-mediated immunity against pathogens. It has also been identified as a major player in a number of chronic inflammatory diseases, including atopic dermatitis.

<span class="mw-page-title-main">Interleukin 25</span> Cytokine that belongs to the IL-17 cytokine family

Interleukin-25 (IL-25) – also known as interleukin-17E (IL-17E) – is a protein that in humans is encoded by the IL25 gene on chromosome 14. IL-25 was discovered in 2001 and is made up of 177 amino acids.

<span class="mw-page-title-main">Interleukin 17</span> Group of proteins

Interleukin 17 family is a family of pro-inflammatory cystine knot cytokines. They are produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. Originally, Th17 was identified in 1993 by Rouvier et al. who isolated IL17A transcript from a rodent T-cell hybridoma. The protein encoded by IL17A is a founding member of IL-17 family. IL17A protein exhibits a high homology with a viral IL-17-like protein encoded in the genome of T-lymphotropic rhadinovirus Herpesvirus saimiri. In rodents, IL-17A is often referred to as CTLA8.

<span class="mw-page-title-main">Interleukin 19</span> Protein-coding gene in the species Homo sapiens

Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.

<span class="mw-page-title-main">STAT6</span> Protein and coding gene in humans

Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor complex to the nucleus and activate gene expression. Similarly as other STAT family proteins, STAT6 is also activated by growth factors and cytokines. STAT6 is mainly activated by cytokines interleukin-4 and interleukin-13.

Pitrakinra is a 15-kDa human recombinant protein of wild-type human interleukin-4 (IL-4). It is an IL-4 and IL-13 antagonist that has been studied in a phase IIb clinical trial for the treatment of asthma. Two point mutations on pitrakinra confer its ability to block signaling of IL-4 and interleukin-13 (IL-13) by preventing assembly of IL-4 receptor alpha (IL-4Rα) with either IL-2Rγ or IL-13Rα. Upregulation of Th2 cytokines, including IL-4 and IL-13, is thought to be critical for the allergic inflammation associated with atopic diseases such as asthma and eczema. The targets of pitrakinra action are inflammatory cells and structural cells that express IL-4Rα. The drug has been applied both as a subcutaneous injection and as an inhalation, but the latter formulation proved to be more effective.

<span class="mw-page-title-main">Interleukin-4 receptor</span> Protein-coding gene in the species Homo sapiens

The interleukin 4 receptor is a type I cytokine receptor. It is a heterodimer, that is, composed of two subunits. IL4R is the human gene coding for IL-4Rα, the subunit which combines with either common gamma chain or with IL-13Rα1.

<span class="mw-page-title-main">Thymic stromal lymphopoietin</span> Cytokine, alarmin, and growth factor.

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-2-like cytokine, alarmin, and growth factor involved in numerous physiological and pathological processes, primarily those of the immune system. It shares a common ancestor with IL-7.

The interleukin-13 receptor is a type I cytokine receptor, binding Interleukin-13. It consists of two subunits, encoded by IL13RA1 and IL4R, respectively. These two genes encode the proteins IL-13Rα1 and IL-4Rα. These form a dimer with IL-13 binding to the IL-13Rα1 chain and IL-4Rα stabilises this interaction. This IL-13 receptor can also instigate IL-4 signalling. In both cases this occurs via activation of the Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway, resulting in phosphorylation of STAT6. Phosphorylated STAT6 dimerises and acts as a transcription factor activating many genes, such as eotaxin.

<span class="mw-page-title-main">Interleukin-17A</span> Protein-coding gene in the species Homo sapiens

Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.

<span class="mw-page-title-main">ILC2</span>

ILC2 cells, or type 2 innate lymphoid cells are a type of innate lymphoid cell. Not to be confused with the ILC. They are derived from common lymphoid progenitor and belong to the lymphoid lineage. These cells lack antigen specific B or T cell receptor because of the lack of recombination activating gene. ILC2s produce type 2 cytokines and are involved in responses to helminths, allergens, some viruses, such as influenza virus and cancer.

In cell biology, TH9 cells are a sub-population of CD4+T cells that produce interleukin-9 (IL-9). They play a role in defense against helminth infections, in allergic responses, in autoimmunity, and tumor suppression.

<span class="mw-page-title-main">Interleukin 17F</span>

Interleukin 17F (IL-17F) is signaling protein that is in human is encoded by the IL17F gene and is considered a pro-inflammatory cytokine. This protein belongs to the interleukin 17 family and is mainly produced by the T helper 17 cells after their stimulation with interleukin 23. However, IL-17F can be also produced by a wide range of cell types, including innate immune cells and epithelial cells.

References

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