Interleukin-31

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

Interleukin-31 (IL-31) is an inflammatory cytokine that belongs to the IL-6 cytokine family. The IL-6 cytokine family includes cytokines 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.

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

Interleukin-31 is encoded by the IL31 gene located on chromosome 12 (gene locus 12:122.17).

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 a significant role in chronic inflammatory processes in the skin (for example, atopic dermatitis, prurigo nodularis), lung of the intestine and nervous system. Tumor cells, T- and B-cell lymphomas, myeloproliferative disorders, also show IL-31 secretion (Ferretti E et al. 2017).

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

These studies demonstrate that interleukin-31 can directly induce pruritogenic signals in peripheral nerves. Thus, interleukin 31 has also been referred to as the "itch cytokine."

Interleukin-31 has become a pharmacological target cytokine (IL-31 antagonists) in diseases associated with pruritus (atopy, prurigo nodularis; cholestasis, uremia).

IL-31 plays a role in chronic inflammatory diseases such as atopic eczema, allergic bronchial asthma, prurigo nodularis, cutaneous amyloidosis and inflammatory bowel diseases. In extrinsic (allergic) bronchial asthma , increased serum levels as well as increased levels in bronchial lavage (here the detection of IL-31 and its receptor IL-31RA can be performed) are detected. The values go in parallel with the degree of severity of asthma and the level of serum IgE .

Atopic dermatitis and prurigo nodularis: A humanized interleukin-31 antibody(nemolizumab) targeting IL-31 receptors, including IL-31 receptors on neurons has been shown to significantly reduce itch and eczema severity with monthly administrations (Ruzicka T et al. (2017).

IL-31 and itch: In general, IL-31 seems to play a significant role in itchy inflammatory skin diseases (atopic dermatitis, prurigo nodularis, cutaneous amyloidosis). In these diseases, increased levels of IL-31 mRNA have been detected in biopsies from lesional skin. In animal experiments, severe pruritus, alopecia and inflammatory skin lesions can be induced by overexpression of IL-31 in transgenic mice. In dogs, itch can also be induced by injection of IL-31.

Furthermore, the cytokine regulates the differentiation of keratinocytes. Inhibition of IL-31 prevents the formation of important structural proteins and lipids of the skin barrier. Due to the disruption of 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 here again in the induction of itch. Mutations in its receptor may also lead to pruritic dermatoses.

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

Prurigo nodularis: Furthermore, a phase 2 study published in the New England Journal of Medicine (NEJM) (Ruzicka T et al 2017) successfully used nemolizumab 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 nearly free of prurigo nodularis, compared with 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

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