Interleukin-31

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

IL31; IL - 31; IL-31; Interleukin 31

Definition
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Interleukins (from Latin/Greek inter = between; leukos = white; kinein = to move) are a group of endogenous, short-chain regulatory proteins (cytokines) of the immune system (IL1-IL38). Interleukins are mediators for induction, course and control of T-cell-mediated cytotoxic immune reactions as well as B-cell activation (antibody production). They are mainly formed and secreted by stimulated leukocytes, monocytes and macrophages. So far, about 38 different interleukins have been clearly identified. Each cytokine of the interleukin group is nomenclatically assigned a number for its classification (IL-1 to IL-38 -level 2017).

Interleukin-31 (IL-31) is an inflammatory cytokine that belongs to the IL-6 cytokine family. The IL-6 cytokine family includes the cytokines IL-6, IL-11, IL-27, leukemia inhibitory factor LIF,oncostatin MOSM, ciliary neurotrophic factor CNTF, cardiotrophin-1 CT-1, cardiotrophin-like cytokine CLC, and neuropoietin NP.

Cytokines of the IL-6 family bind to a receptor complex consisting of IL-31RA and the "oncostatin M receptor beta" also OSMRbeta, which is expressed mainly on immune and epithelial cells. This binding activates the JAK/STAT, PI3K/AKT, p38 mitogen-activated protein kinases, MAPK, extracellular signal-regulated kinase, ERK, and c-Jun N-terminal kinase, JNK signalling pathways.

Interleukin-31 is encoded by the IL-31 gene, which is located on chromosome 12 (gene locus 12:122.17).

General information
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Interleukin-31 is produced and secreted by activated CD4+ T lymphocytes, especially by activated TH2 helper cells, mast cells, macrophages and dendritic cells. Interleukin-31 triggers cellular immunity against pathogens and plays an important role in chronic inflammatory processes in the skin (for example in atopic dermatitis, prurigo nodularis), the lungs of the intestine and the nervous system. Tumor cells, T- and B-cell lymphomas, myeloproliferative diseases, also show IL-31 secretion (Ferretti E et al. 2017).

Interleukin 31 binds to a heterodimeric receptor consisting of the interleukin-31-receptor A and the oncostatin-M-receptorβ subunit OSMRβ Interleukin receptors are found on keratinocytes, on macrophages and eosinophilic granulocytes. Of particular interest is the finding that the IL-31 receptor is most strongly expressed in the sensory nerve cells of the spinal ganglia of the spinal cord. These show an increased co-expression of itching sensors and inflammatory mediators. They are thus able to induce and maintain neurogenic inflammation. Important mediators in this context are TRPV-1 and NPPB. Interleukin 31 also induces phosphorylation and thus activation of the signal transducers of the JAK-STAT signaling pathway JAK1 and JAK2, which are also known as mediators of itching.

This research shows that interleukin 31 can directly induce pruritogenic signals in peripheral nerves. Thus, Interleukin 31 has already been described as an "itching cytokine".

Interleukin-31 is now a pharmacological target cytokine (IL-31 antagonist) for diseases associated with itching (atopy, prurigo nodularis; cholestasis, uremia).

Occurrence
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IL-31 plays a role in chronic inflammatory diseases such as atopic eczema, allergic bronchial asthma and inflammatory bowel diseases.

Interleukin 31 (IL-31) plays an important role in the pathogenesis of allergic diseases. In extrinsic (allergic) bronchial asthma , for example, elevated serum levels are detected as well as elevated levels in bronchial lavage (where IL-31 and its receptor IL-31RA can be detected). The values are accompanied by the degree of severity of the asthma and the level of serum IgE .

Atopic dermatitis and Prurigo nodularis: With a humanized interleukin-31 antibody (nemolizumab), which is applied to IL-31 receptors, including IL-31 receptors on neurons, a significant reduction of itching and eczema severity could be achieved by monthly administration (Ruzicka T et al. (2017).

More generally, IL-31 seems to play an important role in itchy inflammatory skin diseases (atopic dermatitis, prurigo nodularis). In these diseases, increased levels of IL-31 mRNA have been detected in biopsies from lesional skin. In animal experiments, overexpression of IL-31 in transgenic mice can induce severe itching, alopecia and inflammatory skin lesions. Itching can also be induced in dogs by injection of IL-31.

Furthermore, the cytokine regulates the differentiation of keratinocytes. The inhibition of IL-31 prevents the formation of important structural proteins and lipids of the skin barrier. By disturbing the skin barrier, the protection against irritating foreign substances and allergens is significantly reduced.

Versch. variants of the IL-31 gene play a role in the pathogenesis of mastocytosis and again in the induction of itching.

Therapy
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Atopic dermatitis: IL-31 receptor alpha-antibody: Nemolizumab, a first-in-class humanized monoclonal antibody, targets IL-31 receptor alpha, which blocks the signal transduction of IL-31 Chugai Pharmaceutical Co, Ltd. (TOKYO: 4519) recently announced that long-term data from the global Phase II study (264 patients) of nemolizumab (CIM331) showed that nemolizumab is effective in moderate to severe atopic dermatitis (Ruzicka T et al 2017). In the meantime, it has been confirmed that the tolerability and efficacy of nemolizumab was maintained after one year of continuous treatment.

Prurigo nodularis: A Phase 2 study published in the New England Journal of Medicine (NEJM) has also been published in which nemolizumab was successfully used in adult patients with moderate to severe prurigo nodularis (PN). In this study 70 patients were successfully treated with subcutaneous nemolizumab (0.5 mg/kg every 4 weeks). At week 18 (10 weeks after the last dose), 38 percent of patients treated with nemolizumab were free or almost free of prurigo nodularis, compared to 6 percent of patients receiving placebo; P=0.001. Nemolizumab was well tolerated and no imbalance in adverse events was observed between the two groups

Literature
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Last updated on: 29.10.2020