| 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 aprotein that in humans is encoded by theIL31gene that resides on chromosome 12.[5][6][7] IL-31 is aninflammatory cytokine that helps triggercell-mediated immunity against pathogens. It has also been identified as a major player in a number of chronicinflammatory diseases, includingatopic 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 ofIL-31RA andoncostatin M receptor β (OSMRβ) expressed in immune andepithelial cells.[9] These signals activate three pathways:ERK1/2 MAP kinase,PI3K/AKT, andJAK1/2 signaling pathways.[7][8]
IL-31 is acytokine with an anti-parallelfour-helix bundle structure in the gp130/IL-6 cytokine family.[7] This family includesIL-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 throughtype I cytokine receptors. Type I cytokine receptors are defined by sharing their cytokine binding domain (CBD) with conservedcysteine residues and a conservedWSxWS motif in the extracellular domain.[7] The receptors form heteromeric complexes that usually contain theglycoprotein 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 theinterleukin 31 receptor alpha (IL-31RA) andOSMR.[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) andoncostatin M receptor (OSMR) subunits. These receptor subunits are expressed in activatedmonocytes and in unstimulatedepithelial 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 activateSTAT1,STAT3, andSTAT5.[7] The OSMR portion of the IL-31 binding complex contains intracellular motifs box1 and box2.[7] This allows forJAK1 andJAK2 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 thePI3K/AKT signaling pathway.[7] In contrast to IL-31RA, which bindsSHP-2, the OSMR interacts with the adaptor proteinShc 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 betranscribed.
Interleukin 31 is aninflammatory cytokine produced by activatedCD4+T lymphocytes, in particular activatedTH2 helper cells,mast cells,macrophages, anddendritic cells. It major sites of action are the skin, lung, intestine and the nervous system.[10] Hence IL-31 main role is to facilitatecell-mediated immunity against pathogens.
IL-31 and its receptors are also involved in regulatinghematopoietic progenitor cell homeostasis.[8]
IL-31 is believed to play a role in chronicinflammation diseases.[6][9] One of these diseases isatopic 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 genesCCL1,CCL17, andCCL22.[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 sensoryneurons 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.
Amonoclonal antibody against IL-31 namedlokivetmab is available for the treatment of canine atopic dermatitis.[11]
