Interleukin 31

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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.[1][2][3] 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.[3][4]

IL-31 is produced by a variety of cells, namely type 2 helper (TH2) T-cells.[3] IL-31 sends signals through a receptor complex made of IL-31RA and oncostatin M receptor β (OSMRβ) expressed in immune and epithelial cells.[5] These signals activate three pathways: ERK1/2 MAP kinase, PI3K/AKT, and JAK1/2 signaling pathways.[3][4]

Structure

IL-31 is a cytokine with an anti-parallel four-helix bundle structure in the gp130/IL-6 cytokine family.[3] 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).[4] 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.[3] 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.[3] The receptors form heteromeric complexes that usually contain the glycoprotein 130 (gp130), which is important for activating downstream signaling pathways.[3] 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.[3] IL-31RA was originally referred to as GLM-R (for gp130-like monocyte receptor) or GPL (for gp130-like receptor).[3] Although the IL-31 receptor complex lacks gp130, IL-31RA has similarities to gp130 like its previous descriptors suggest.

Signaling

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.[1] 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 a intracellular domain that possesses a box1 motif that mediates association with kinases of the JAK family.[3] 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.[3] The OSMR portion of the IL-31 binding complex contains intracellular motifs box1 and box2.[3] This allows for JAK1 and JAK2 to bind, which are recruited once the tyrosine residues on the intracellular domain are phosphorylated.[3] 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.[3] 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.[3] 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.

Function

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.[6] 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.[4]

Clinical significance

IL-31 is believed to play a role in chronic inflammation diseases.[2][5] 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.[4] 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.[4]

Pruritic forms of inflammatory skin diseases, or itchy skin diseases, have been found to have elevated levels of IL-31 mRNA in patient biopsies.[4] 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.[4] 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.[4] 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.[7]

References

  1. 1.0 1.1 "Entrez Gene: interleukin 31".
  2. 2.0 2.1 Dillon SR, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR, et al. (July 2004). "Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice". Nature Immunology. 5 (7): 752–60. doi:10.1038/ni1084. PMID 15184896.
  3. 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 Cornelissen C, Lüscher-Firzlaff J, Baron JM, Lüscher B (June 2012). "Signaling by IL-31 and functional consequences". European Journal of Cell Biology. 91 (6–7): 552–66. doi:10.1016/j.ejcb.2011.07.006. PMID 21982586.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Zhang Q, Putheti P, Zhou Q, Liu Q, Gao W (October 2008). "Structures and biological functions of IL-31 and IL-31 receptors". Cytokine & Growth Factor Reviews. 19 (5–6): 347–56. doi:10.1016/j.cytogfr.2008.08.003. PMC 2659402. PMID 18926762.
  5. 5.0 5.1 Rabenhorst A, Hartmann K (April 2014). "Interleukin-31: a novel diagnostic marker of allergic diseases". Current Allergy and Asthma Reports. 14 (4): 423. doi:10.1007/s11882-014-0423-y. PMID 24510535.
  6. Hermanns HM (2015). "Oncostatin M and interleukin-31: Cytokines, receptors, signal transduction and physiology". Cytokine & Growth Factor Reviews. 26 (5): 545–58. doi:10.1016/j.cytogfr.2015.07.006. PMID 26198770.
  7. Hilde Moyaert et al.: A blinded, randomized clinical trial evaluationg the efficacy and safety of lokivetmab compared to ciclosporin in client owned dogs with atopic dermatitis. In: Vet. Dermatology, September 2017 doi:10.1111/vde.12478

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