Interleukin-13 receptor

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interleukin 13 receptor, alpha 1
Identifiers
Symbol IL13RA1
Alt. symbolsIL-13Ra, NR4, CD213a1
NCBI gene 3597
HGNC 5974
OMIM 300119
RefSeq NM_001560
UniProt P78552
Other data
Locus Chr. X q24
Search for
Structures Swiss-model
Domains InterPro
interleukin 13 receptor, alpha 2
Identifiers
Symbol IL13RA2
Alt. symbolsIL-13R, IL13BP, CD213a2
NCBI gene 3598
HGNC 5975
OMIM 300130
RefSeq NM_000640
UniProt Q14627
Other data
Locus Chr. X q13.1-q28
Search for
Structures Swiss-model
Domains InterPro
interleukin 4 receptor
Identifiers
Symbol IL4R
Alt. symbolsIL4RA; CD124
NCBI gene 3566
HGNC 6015
OMIM 147781
RefSeq NM_000418
UniProt Q9H186
Other data
Locus Chr. 16 p12.1-11.2
Search for
Structures Swiss-model
Domains InterPro

The interleukin-13 receptor is a type I cytokine receptor, binding Interleukin-13. It consists of two subunits, encoded by IL13RA1 and IL4R, respectively. [1] [2] 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. [ citation needed ]

Contents

There is also another receptor that can bind IL-13: IL-13Rα2 encoded by the IL13RA2 gene. This binds IL-13 with very high affinity (and can therefore sequester it) but does not allow IL-4 binding. It acts as a negative regulator of both IL-13 and IL-4, however the mechanism of this is still undetermined. [3]

Function

Interleukin 13 (IL-13) is an effector cytokine partially sharing the signaling pathways with IL-4 due to the utilization of a common receptor system (IL-4 receptor type II). A “private” receptor system, binding specifically IL-13 with high affinity, seems to use different signalling pathways and is increasingly being studied for its potential as a novel prognostic factor, biomarker or therapeutic target in different types of cancer. [4] [5] [6] [7]

The “shared” IL-4 / IL-13 receptor

IL-13 uses the IL-4 receptor type II (IL-4RII), a complex formed by an IL-4Rα chain and an IL-13Rα1 chain. Initially, the ligand (IL-4 or IL-13) binds to the IL-4Rα chain and IL-13Rα1 respectively; thereafter, a secondary chain (IL-13Rα1 and IL-4Rα respectively) will also bind, forming the complete IL-4RII. The IL-4/IL-4Rα complex, however, can also bind to a different secondary chain, the IL-2Rγc, forming the IL-4 receptor type I (IL-4RI). [8] In non-hematopoietic cells, IL-2Rγc is poorly expressed; on the other hand, IL-13Rα1 is poorly expressed in lymphocytes but abundantly in all non-hematopoietic cells; myeloid cells express both of them to a certain degree. This different distribution of secondary chains accounts for the difference in distribution of completed receptors, with being IL-4RI prevalently expressed in lymphocyte, and IL-4RII prevalently in non-hematopoietic cells. Consequently, only IL-4, through IL-4R1, is able to modulate the function of lymphocytes inducing Th2 polarisation and B cells IgG1/IgE class switching, while IL-13 is mainly acting on myeloid cells and non-hematopoietic cells, having strong effects on mucus production, smooth muscle contraction, epithelium permeabilisation (e.g. allergic asthma). [9] After the complete assemblage, the conformational changes in IL-4RI or IL-4RII tails leads to the intracellular signaling, starting with the auto and cross-phosphorylation of associated Jak kinases (Jak3 for IL-2Rγc, Jak1 for IL-4Rα, Jak2 and Tyk2 for IL-13Rα1), [10] and followed by phosphorylation of intracellular domains of IL-4Rα in critical Y residues which are therefore activated to form the docking sites for downstream signalling molecules endowed with SH domains. [8] While the docking sites in IL-4R1 (and consequently IL-4) are able to efficiently activate both STAT6 and IRS2 signalling molecules, IL-4RII (and consequently IL-13) only activates effectively STAT6. [11] Activated STAT6 molecules form dimers which translocate to the nucleus to bind responsive elements (e.g. CD23 promoter in B cells, [12] arginase1 enhancer in macrophages [13] ) The binding affinity of IL-4 for IL-4Rα is much higher than IL-13 for the IL-13Rα1, hence IL-4 would out-compete IL-13 for receptor availability within IL4R2 at parity of concentration. [14]

The “private” IL-13 receptor

Besides IL-13Rα1 chain (which work in conjunction with the IL-4Rα, IL-13 can bind with much higher affinity to IL-13Rα2. IL-13Rα2 presents 35% homology with IL-13Rα1 and it is expressed mostly in structural cell (but also has been identified in fibroblasts and, only in mice, in soluble form). It presents an extraordinary affinity to IL-13, but does not form complexes with any secondary chain. [14] Because of the apparent lack of signaling domain and the short tail, it has been initially thought not to have any signaling activity, and regarded as “decoy” receptor, that is its function would just consist in competing for IL-13 binding and neutralizing his effect. Indeed, it has been shown that IL-13Rα2 blocks IL-13 driven STAT6 signalling by binding IL-13 with high affinity, however a partial block is also extending to IL-4 driven STAT6 signalling, presumably due to the cytoplasmic domain interfering with the assembling of IL-4/IL-4Rα with a secondary chain. [15] [16] However, increasing evidences are accumulating that IL-13Rα2 is more than a “decoy”. IL-13 signalling through IL-13Rα2 and AP1-driven TGF-β production has been initially reported in monocytes and then confirmed in mouse models. [17] [18] According these studies, IL-13, through the over-expression (TNF-α induced) of IL-13Rα2 would be able to activate AP-1 signalling and production of TGF-β, driving pro-fibrotic effects. Some recent works is evidencing how a wide range of signals can be actually activated by this receptor (e.g. WNT/β-Catenin, MAPK/ERK, AKT/PKB, Src/FAK, PIP3K ) in normal or pathologic environments. How IL-13Rα2 might overcome the limitation of a 17 aminoacids short tail lacking any signalling motif, it is not clear yet but it has been shown that, at least in some cases, the association with other receptors or signalling adaptors can do the trick. [19] [20]

Related Research Articles

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B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors. When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. In addition, B cells present antigens and secrete cytokines. In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the B stands for bursa and not bone marrow, as commonly believed.

The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through the process of transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors. Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.

<span class="mw-page-title-main">Interleukin 2</span> Mammalian protein found in Homo sapiens

Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a 15.5–16 kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for immunity. IL-2 is part of the body's natural response to microbial infection, and in discriminating between foreign ("non-self") and "self". IL-2 mediates its effects by binding to IL-2 receptors, which are expressed by lymphocytes. The major sources of IL-2 are activated CD4+ T cells and activated CD8+ T cells. Put shortly the function of IL-2 is to stimulate the growth of helper, cytotoxic and regulatory T cells.

<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.

<span class="mw-page-title-main">Interleukin 3</span> Protein-coding gene in the species Homo sapiens

Interleukin 3 (IL-3) is a protein that in humans is encoded by the IL3 gene localized on chromosome 5q31.1. Sometimes also called colony-stimulating factor, multi-CSF, mast cell growth factor, MULTI-CSF, MCGF; MGC79398, MGC79399: the protein contains 152 amino acids and its molecular weight is 17 kDa. IL-3 is produced as a monomer by activated T cells, monocytes/macrophages and stroma cells. The major function of IL-3 cytokine is to regulate the concentrations of various blood-cell types. It induces proliferation and differentiation in both early pluripotent stem cells and committed progenitors. It also has many more specific effects like the regeneration of platelets and potentially aids in early antibody isotype switching.

<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

In immunology, an Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.

<span class="mw-page-title-main">Interleukin 13</span> Protein and coding gene in humans

Interleukin 13 (IL-13) is a protein that in humans is encoded by the IL13 gene. IL-13 was first cloned in 1993 and is located on chromosome 5q31.1 with a length of 1.4kb. It has a mass of 13 kDa and folds into 4 alpha helical bundles. 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. 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. Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation. It is a mediator of allergic inflammation and different diseases including asthma.

<span class="mw-page-title-main">IL-2 receptor</span> Lymphocyte receptor specific for Interleukin-2

The interleukin-2 receptor (IL-2R) is a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to a cytokine called IL-2.

<span class="mw-page-title-main">Interleukin 15</span> Cytokine with structural similarity to Interleukin-2

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<span class="mw-page-title-main">Interleukin 22</span> Protein, encoded in humans by IL22 gene

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

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

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References

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