IL31 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Aliases | IL31 , IL-31, interleukin 31 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 609509; MGI: 1923649; HomoloGene: 88541; GeneCards: IL31; OMA:IL31 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Interleukin-31 (IL-31) is a protein that in humans is encoded by the IL31 gene that resides on chromosome 12. [5] [6] [7] 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. [7] [8]
IL-31 is produced by a variety of cells, namely type 2 helper (TH2) T-cells. [7] IL-31 sends signals through a receptor complex made of IL-31RA and oncostatin M receptor β (OSMRβ) expressed in immune and epithelial cells. [9] These signals activate three pathways: ERK1/2 MAP kinase, PI3K/AKT, and JAK1/2 signaling pathways. [7] [8]
IL-31 is a cytokine with an anti-parallel four-helix bundle structure in the gp130/IL-6 cytokine family. [7] This family includes IL-6, IL-11, IL-27, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), and neuropoietin (NP). [8] The anti-parallel bundles that these proteins form have an "up-up-down-down" topology, which is a relevant structure regarding the cytokine binding to their respective receptor complex. [7] The cytokines in the IL-6 family signal through type I cytokine receptors. Type I cytokine receptors are defined by sharing their cytokine binding domain (CBD) with conserved cysteine residues and a conserved WSxWS motif in the extracellular domain. [7] The receptors form heteromeric complexes that usually contain the glycoprotein 130 (gp130), which is important for activating downstream signaling pathways. [7] IL-31 is unique in this family of cytokines because its receptor complex does not contain gp130. The receptor for IL-31 is a heterodimer of the interleukin 31 receptor alpha (IL-31RA) and OSMR. [7] IL-31RA was originally referred to as GLM-R (for gp130-like monocyte receptor) or GPL (for gp130-like receptor). [7] Although the IL-31 receptor complex lacks gp130, IL-31RA has similarities to gp130 like its previous descriptors suggest.
IL-31 signals via a receptor complex that is composed of IL-31 receptor A (IL31RA) and oncostatin M receptor (OSMR) subunits. These receptor subunits are expressed in activated monocytes and in unstimulated epithelial cells. [5] IL-31RA binds IL-31 through its cytokine binding domain (CBD). OSMR does not normally bind to IL-31 but it does increase the IL-31 binding affinity to IL-31RA. IL-31RA has an intracellular domain that possesses a box1 motif that mediates association with kinases of the JAK family. [7] Additionally, the intracellular portion of the IL-31RA contains tyrosine residues. When IL-31 binds to the receptor complex, JAK kinases are activated which phosphorylate and activate STAT1, STAT3, and STAT5. [7] The OSMR portion of the IL-31 binding complex contains intracellular motifs box1 and box2. [7] This allows for JAK1 and JAK2 to bind, which are recruited once the tyrosine residues on the intracellular domain are phosphorylated. [7] Through these phosphorylation sites, STAT3 and STAT5 are recruited and phosphorylated by JAK1 and JAK2. In addition to STATs, PI3K is recruited, which stimulates the PI3K/AKT signaling pathway. [7] In contrast to IL-31RA, which binds SHP-2, the OSMR interacts with the adaptor protein Shc via the phosphorylated tyrosines on its intracellular domain. Through Shc, the RAS/RAF/MEK/ERK pathway is activated along with the p38 and JNK pathways. [7] When IL-31 binds to the IL-31RA/OSMR complex, the JAK, PI3K/AKT, and ERK signaling pathways are activated. The pathways allow for target genes to be transcribed.
Interleukin 31 is an inflammatory cytokine produced by activated CD4+ T lymphocytes, in particular activated TH2 helper cells, mast cells, macrophages, and dendritic cells. It major sites of action are the skin, lung, intestine and the nervous system. [10] Hence IL-31 main role is to facilitate cell-mediated immunity against pathogens.
IL-31 and its receptors are also involved in regulating hematopoietic progenitor cell homeostasis. [8]
IL-31 is believed to play a role in chronic inflammation diseases. [6] [9] One of these diseases is atopic dermatitis, or eczema. When biopsy samples of patients with atopic dermatitis were compared to samples from patients without atopic dermatitis, levels of IL-31 were elevated in patients with atopic dermatitis. IL-31 plays a role in this disease by inducing chemokine genes CCL1, CCL17, and CCL22. [8] The chemokines transcribed from these genes recruit T-cells to the irritated skin where they secrete more IL-31. This cycle is the current understanding of IL-31's role in atopic dermatitis. Along with atopic dermatitis, IL-31 is believed to play a role in inflammatory bowel disease and airway hypersensitivity. [8]
Pruritic forms of inflammatory skin diseases, or itchy skin diseases, have been found to have elevated levels of IL-31 mRNA in patient biopsies. [8] Analysis of the tissue distribution of the IL-31 receptor complex found that IL-31RA is abundant in dorsal root ganglia of different human tissues. [8] Dorsal root ganglia is where the cell bodies of primary sensory neurons reside. Dorsal root ganglia are also believed to be where the "itch" sensation originates. [8] These findings support the elevated levels of IL-31 in skin biopsies of pruritic skin diseases.
A monoclonal antibody against IL-31 named lokivetmab is available for the treatment of canine atopic dermatitis. [11]
Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2, but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman god of beginnings, endings and duality, Janus, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other negatively regulates the kinase activity of the first.
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.
Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the IL6 gene.
Interferon gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed interferon gamma release assay used to test for tuberculosis. In humans, the IFNG protein is encoded by the IFNG gene.
Oncostatin M, also known as OSM, is a protein that in humans is encoded by the OSM gene.
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.
Glycoprotein 130 is a transmembrane protein which is the founding member of the class of tall cytokine receptors. It forms one subunit of the type I cytokine receptor within the IL-6 receptor family. It is often referred to as the common gp130 subunit, and is important for signal transduction following cytokine engagement. As with other type I cytokine receptors, gp130 possesses a WSXWS amino acid motif that ensures correct protein folding and ligand binding. It interacts with Janus kinases to elicit an intracellular signal following receptor interaction with its ligand. Structurally, gp130 is composed of five fibronectin type-III domains and one immunoglobulin-like C2-type (immunoglobulin-like) domain in its extracellular portion.
The interferon-gamma receptor (IFNGR) protein complex is the heterodimer of two chains: IFNGR1 and IFNGR2. It binds interferon-γ, the sole member of interferon type II.
GRB2-associated-binding protein 2 also known as GAB2 is a protein that in humans is encoded by the GAB2 gene.
Oncostatin-M specific receptor subunit beta also known as the Oncostatin M receptor (OSMR), is one of the receptor proteins for oncostatin M, that in humans is encoded by the OSMR gene.
Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the TYK2 gene.
JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family, the IL-4 receptor family, the gp130 receptor family. It is also important for transducing a signal by type I (IFN-α/β) and type II (IFN-γ) interferons, and members of the IL-10 family via type II cytokine receptors. Jak1 plays a critical role in initiating responses to multiple major cytokine receptor families. Loss of Jak1 is lethal in neonatal mice, possibly due to difficulties suckling. Expression of JAK1 in cancer cells enables individual cells to contract, potentially allowing them to escape their tumor and metastasize to other parts of the body.
Interleukin 20 receptor, alpha subunit, is a subunit of the interleukin-20 receptor, the interleukin-26 receptor, and the interleukin-24 receptor. The interleukin 20 receptor, alpha subunit is also referred to as IL20R1 or IL20RA. The IL20RA receptor is involved in both pro-inflammatory and anti-inflammatory responses, signaling through the JAK-STAT pathway.
Interleukin-31 receptor A is a protein that in humans is encoded by the IL31RA gene.
Interleukin 20 receptor, beta subunit is a subunit of the interleukin-20 receptor and interleukin-22 receptor. It is believed to be involved in both pro-inflammatory and anti-inflammatory responses.
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.
Interleukin-10 receptor (IL-10R) is a type II cytokine receptor. The receptor is tetrameric, composed of 2α and 2β subunits. The α subunit is expressed on haematopoietic cells whilst the β subunit is expressed ubiquitously. The α subunit is exclusive to interleukin-10, however the β subunit is shared with other type II cytokine receptors such as IL-22R, IL-26R and INFλR.
Interleukin 20 receptors (IL20R) belong to the IL-10 family. IL20R are involved in both pro-inflammatory and anti-inflammatory immune response. There are two types of IL20R: Type I and Type II.
Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A, Interleukin-28B, interleukin 29 and interferon lambda 4. It consists of an α chain and shares a common β subunit with the interleukin-10 receptor. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.
The interleukin-2 receptor alpha chain is a protein involved in the assembly of the high-affinity interleukin-2 receptor, consisting of alpha (IL2RA), beta (IL2RB) and the common gamma chain (IL2RG). As the name indicates, this receptor interacts with interleukin-2, a pleiotropic cytokine which plays an important role in immune homeostasis.