Interleukin-31 (IL-31) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''IL31''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

that resides on chromosome 12. IL-31 is an

inflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include int ...

that helps trigger cell-mediated immunity against pathogens. It has also been identified as a major player in a number of chronic

inflammatory disease Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants. The five cardinal signs are heat, pain, redness, swelling, and Functio laesa, loss of funct ...

s, including

atopic dermatitis Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin. Atopic dermatitis is also often called simply eczema but the same term is also used to refer to dermatitis, the larger group of skin conditi ...

. IL-31 is produced by a variety of cells, namely type 2 helper ( T_H2) T-cells. IL-31 sends signals through a receptor complex made of IL-31RA and oncostatin M receptor β (OSMRβ) expressed in immune and

epithelial cell Epithelium or epithelial tissue is a thin, continuous, protective layer of Cell (biology), cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial (Mesothelium, mesothelial) tissues line ...

s. These signals activate three pathways: ERK1/2 MAP kinase, PI3K/AKT, and JAK1/ 2 signaling pathways.

Structure

IL-31 is a

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

with an anti-parallel four-helix bundle structure in the gp130/IL-6 cytokine family. 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). 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. The cytokines in the IL-6 family signal through

type I cytokine receptor Type I cytokine receptors are transmembrane receptors expressed on the surface of cells that recognize and respond to cytokines with four α-helical strands. These receptors are also known under the name '' hemopoietin receptors'', and share a ...

s. Type I cytokine receptors are defined by sharing their cytokine binding domain (CBD) with conserved

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

residues and a conserved WSxWS motif in the extracellular domain. The receptors form heteromeric complexes that usually contain the glycoprotein 130 (gp130), which is important for activating downstream signaling pathways. 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. IL-31RA was originally referred to as GLM-R (for gp130-like monocyte receptor) or GPL (for gp130-like receptor). 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 Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...

and in unstimulated

epithelial cells Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

. 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. 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 Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the ''STAT1'' gene. It is a member of the STAT protein family. Function All STAT molecules are phosphorylated by receptor associ ...

STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respon ...

, and STAT5. The OSMR portion of the IL-31 binding complex contains intracellular motifs box1 and box2. This allows for JAK1 and

JAK2 Janus kinase 2 (commonly called JAK2) is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors), the GM-CSF ...

to bind, which are recruited once the tyrosine residues on the intracellular domain are phosphorylated. Through these phosphorylation sites, STAT3 and STAT5 are recruited and phosphorylated by JAK1 and JAK2. In addition to STATs,

PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

is recruited, which stimulates the PI3K/AKT signaling pathway. In contrast to IL-31RA, which binds

SHP-2 Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in hu ...

, 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. 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

produced by activated CD4⁺

T lymphocyte T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...

s, in particular activated T_H2 helper cells,

mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a p ...

macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

s, and

dendritic cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...

s. It major sites of action are the skin, lung, intestine and the nervous system. Hence IL-31 main role is to facilitate cell-mediated immunity against pathogens. IL-31 and its receptors are also involved in regulating

hematopoietic Haematopoiesis (; ; also hematopoiesis in American English, sometimes h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten ...

progenitor cell homeostasis.

Clinical significance

IL-31 is believed to play a role in chronic

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

diseases. One of these diseases is

, 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. 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.

Pruritic An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both a ...

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

Dorsal root ganglia A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the dors ...

is where the cell bodies of primary sensory

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

s reside. Dorsal root ganglia are also believed to be where the "itch" sensation originates. These findings support the elevated levels of IL-31 in skin biopsies of pruritic skin diseases. A

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodie ...

against IL-31 named lokivetmab is available for the treatment of canine atopic dermatitis.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

References

{{Interleukin receptor modulators Interleukins