Interleukin 31

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 T_H2 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]