IL31 - interleukin 31 |Elisa - Clia - Antibody - Protein

Background

Interleukin 31 (IL-31) is a cytokine belonging to the IL-6 cytokine family that plays a central role in the regulation of immune responses and is heavily implicated in inflammatory processes, particularly in chronic pruritic (itching) skin disorders. IL-31 is primarily produced by activated T helper 2 (Th2) cells, a subset of T cells involved in allergic responses and the regulation of immune responses to extracellular pathogens. IL-31 was discovered as a cytokine that can link the immune system with the nervous system, particularly in the skin, where it triggers pruritus and inflammatory responses.

The IL-31 receptor is widely expressed, being found on keratinocytes, fibroblasts, epithelial cells, and immune cells, which suggests its involvement in skin and tissue homeostasis. In particular, IL-31 is associated with the pathogenesis of atopic dermatitis (AD) and allergic diseases, where it induces the release of pro-inflammatory cytokines and enhances itching, making it a key target for therapeutic interventions.

Protein Structure

IL-31 is a monomeric cytokine composed of 164 amino acids. It shares structural features with the IL-6 family of cytokines, which includes IL-6, IL-11, IL-27, and others. Like these family members, IL-31 contains the characteristic four-helix bundle motif, which is a common structure in long-chain cytokines. This four-helix bundle consists of α-helices that are arranged in an up-up, down-down configuration, providing the basis for receptor interaction.

Structurally, IL-31 engages its receptor complex via two receptor subunits:

• IL-31 receptor alpha (IL-31RA)
• Oncostatin M receptor beta (OSMRβ).

Both receptor subunits are members of the gp130 family of receptors and mediate IL-31 signaling through their cytoplasmic tails, which initiate intracellular signaling cascades.

Receptor Complex:

1. IL-31RA: This is the primary binding receptor for IL-31. It is a type I cytokine receptor with fibronectin type III domains that are critical for ligand binding. Once bound to IL-31, IL-31RA associates with OSMRβ to form the complete receptor complex.
2. OSMRβ: This receptor subunit also participates in signaling for other cytokines, such as oncostatin M, which further highlights the shared signaling pathways within the IL-6 family. OSMRβ enhances the downstream signaling of IL-31.

Upon binding to IL-31, the IL-31RA and OSMRβ complex activates downstream signaling pathways, primarily involving the JAK/STAT pathway, but also the MAPK/ERK and PI3K/AKT pathways, resulting in transcriptional changes that mediate the effects of IL-31 on target cells.

Classification and Subtypes

IL-31 is classified within the IL-6 family of cytokines, which share structural and functional similarities. However, unlike some cytokines in this family that form heterodimers or heterotrimers, IL-31 is a monomeric cytokine that forms a functional unit with its receptor complex.

IL-31 does not have specific subtypes; however, its functions and effects can vary depending on the tissue or cell type expressing the receptor, as well as the presence of other cytokines that can modulate its activity. IL-31-related signaling may also cross-talk with other cytokine pathways, particularly those involving Th2 cytokines like IL-4 and IL-13, which are central in allergic inflammation and atopic dermatitis.

Function and Biological Significance

IL-31 plays a major role in regulating inflammatory responses, particularly in skin and barrier tissues. Its primary function revolves around its ability to mediate pruritus (itch), inflammation, and the release of pro-inflammatory mediators from immune cells and epithelial cells. The primary biological functions of IL-31 include:

Induction of Pruritus (Itch):

• IL-31 is best known for its role in inducing itching, particularly in the context of atopic dermatitis and other pruritic skin disorders. IL-31 stimulates the release of pruritogenic factors, such as histamines and neuropeptides, from mast cells and neurons, enhancing the sensation of itch.
• Additionally, IL-31 interacts with sensory neurons in the skin to directly induce neuronal activation, leading to the transmission of itching signals to the central nervous system.

Regulation of Skin Inflammation:

• IL-31 promotes inflammation by stimulating the production of pro-inflammatory cytokines and chemokines from keratinocytes and fibroblasts. This leads to the recruitment of additional immune cells to the site of inflammation, including eosinophils, macrophages, and T cells.
• IL-31-mediated inflammation is critical in the development and maintenance of chronic skin conditions, such as atopic dermatitis and psoriasis, where persistent inflammation and tissue damage occur.

Barrier Dysfunction:

• IL-31 can disrupt epithelial barrier function, particularly in the skin. By altering the integrity of tight junctions and reducing the production of structural proteins like filaggrin, IL-31 exacerbates barrier dysfunction, making the skin more susceptible to allergens and irritants, thereby perpetuating the inflammatory cycle.

Th2-mediated Immune Response:

• IL-31 is often associated with the Th2 immune response, a pathway involved in allergic reactions. Th2 cells, which produce cytokines such as IL-4, IL-5, and IL-13, are important in allergic inflammation. IL-31 works in concert with these cytokines to drive immune responses in diseases such as atopic dermatitis and asthma.

Fibrosis and Tissue Remodeling:

• IL-31 may play a role in fibrosis and tissue remodeling, particularly in chronic skin diseases and potentially in lung or other organ systems. It stimulates fibroblasts to produce extracellular matrix proteins, contributing to tissue thickening and fibrosis.

Clinical Issues

IL-31 is implicated in several diseases, most notably pruritic skin disorders and conditions associated with chronic inflammation.

Atopic Dermatitis (AD):

• IL-31 is strongly associated with atopic dermatitis, a chronic inflammatory skin disease characterized by severe pruritus (itching) and eczematous lesions. Elevated levels of IL-31 are found in the serum and skin lesions of patients with AD, and IL-31 levels correlate with disease severity. IL-31 directly induces itching by stimulating sensory neurons and contributes to the inflammatory environment by activating keratinocytes and immune cells.

Chronic Pruritus:

• Beyond atopic dermatitis, IL-31 plays a critical role in other chronic pruritic conditions, including prurigo nodularis, a skin disease characterized by intensely itchy nodules, and uremic pruritus, a condition seen in patients with chronic kidney disease. Therapeutically targeting IL-31 is seen as a promising approach to managing these chronic pruritic conditions.

Allergic Diseases:

• IL-31 is implicated in allergic asthma, where its expression is associated with Th2-dominant inflammation and airway remodeling. Elevated IL-31 levels have been reported in asthmatic patients, and it may contribute to the pathophysiology of airway hyperreactivity and mucus hypersecretion.

Psoriasis:

• Although traditionally associated with Th1/Th17 inflammation, psoriasis patients also exhibit elevated levels of IL-31, suggesting that it may contribute to the chronic pruritus observed in some cases of psoriasis. Its exact role in the disease remains to be fully elucidated.

Potential Therapeutic Targeting:

• Given IL-31's key role in mediating itch and inflammation, it has emerged as a target for therapeutic intervention. Anti-IL-31 monoclonal antibodies, such as nemolizumab, have shown promise in clinical trials for treating atopic dermatitis and other pruritic conditions by reducing itch and improving quality of life in patients.

Summary

Interleukin 31 (IL-31) is a critical cytokine in the IL-6 family with central roles in regulating immune responses, skin inflammation, and pruritus. Structurally, IL-31 is a monomeric protein with a four-helix bundle that binds to a heterodimeric receptor composed of IL-31RA and OSMRβ. Through activation of the JAK/STAT, MAPK/ERK, and PI3K/AKT pathways, IL-31 regulates gene expression that promotes inflammatory responses, itching, and barrier dysfunction.

Clinically, IL-31 is most notably involved in atopic dermatitis and chronic pruritus, where it contributes to both itching and skin inflammation. Targeting IL-31 therapeutically, especially with monoclonal antibodies, represents a promising strategy for managing chronic skin diseases associated with inflammation and itching, providing a better understanding of its biological significance and potential clinical benefits.