Interleukin-31

Interleukins (from Latin inter = "between" and Greek λευκός (leukós) = "white" and κινεῖν (kinein) = "to move", "to set in motion") are a group of short-chain regulatory proteins (cytokines) of the immune system (IL1-IL38). Interleukins are mediators for the induction, progression and control of T-cell-mediated cytotoxic immune reactions and B-cell activation (antibody production). They are mainly produced and secreted by stimulated leukocytes, monocytes and macrophages. To date, around 38 different interleukins have been clearly identified. Each cytokine in the interleukin group is nomenclaturally 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 the cytokines IL-6, IL-11, IL-27, the "leukemia inhibitory factor" LIF, the "oncostatin M" OSM, the "ciliary neurotrophic factor" CNTF, the "cardiotrophin-1" CT-1, the "cardiotrophin-like cytokine" CLC, and the "neuropoietin" NP.

Cytokines of the IL-6 family bind to a receptor complex consisting of IL-31RA (IL-31 receptor-α) and the subunit oncostatin M receptor-β (OSMRβ). This receptor complex is mainly expressed on immune cells and epithelial cells. Ligand binding leads to the activation of several intracellular signaling pathways, including the JAK/STAT pathway, the PI3K/AKT pathway, the p38 mitogen-activated protein kinase (p38-MAPK), the extracellular signal-regulated kinase (ERK) and the c-Jun-N-terminal kinase (JNK).

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

Interleukin-31 is produced and secreted by activated CD4-positive T lymphocytes, especially by activated type 2 T helper cells (_TH2lymphocytes), 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 and prurigo nodularis), the lungs, the intestines and the nervous system. Tumor cells, T- and B-cell lymphomas and 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 receptor β subunit OSMRβ. Interleukin receptors are found on keratinocytes, macrophages and eosinophil granulocytes. Of particular interest is the finding that the IL-31 receptor is most strongly expressed in the sensory nerve cells of the dorsal root ganglia of the spinal cord. These show 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. Interleukin-31 also induces the phosphorylation and thus activation of the signal transducers of the JAK-STAT signaling pathway JAK1 and JAK2, which are also known mediators of itching.

These studies show that interleukin-31 can directly induce pruritogenic signals in peripheral nerves. Interleukin-31 has therefore already been referred to as the "itch cytokine".

Interleukin-31 is now a pharmacological target cytokine (IL-31 antagonists) in diseases associated with pruritus (atopy, prurigo nodularis; cholestasis, uraemia).

IL-31 plays a role in chronic inflammatory diseases, e.g. atopic eczema, allergic bronchial asthma, prurigo nodularis, cutaneous amyloidosis and inflammatory bowel diseases. In extrinsic (allergic) bronchial ast hma, increased serum levels are detected, as are increased levels in the bronchial lavage (IL-31 and its receptor IL-31RA can be detected here). The values are directly correlated with the severity of the asthma and the level of serum IgE .

Atopic dermatitis and prurigo nodularis: With a humanized interleukin-31 antibody(nemolizumab), which binds to IL-31 receptors, including the IL-31 receptors on neurons, a significant reduction in itching and eczema severity was achieved by monthly administration (Ruzicka T et al. (2017).

IL-31 and itching: In general, IL-31 appears to play an important 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, overexpression of IL-31 in transgenic mice can induce severe itching, alopecia and inflammatory skin lesions. Itching can also be induced in dogs by injecting IL-31.

The cytokine also regulates the differentiation of keratinocytes. The inhibition of IL-31 prevents the formation of important structural proteins and lipids of the skin barrier. The disruption of the skin barrier significantly reduces protection against irritating foreign substances and allergens.

Versch. Variants of the IL-31 gene play a role in the pathogenesis of mastocytosis and again in the induction of itching. Mutations in its receptor can also lead to itchy dermatoses.

Atopic dermatitis: Nemolizumab is a first-in-class, humanized monoclonal antibody that specifically blocks IL-31 receptor alpha and thereby inhibits IL-31 signaling. Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported the results of a global Phase II study involving 264 patients. In this study, nemolizumab was shown to be effective in patients with moderate to severe atopic dermatitis (Ruzicka T. et al., 2017). In the meantime, it has also been confirmed that both efficacy and tolerability are maintained even after one year of continuous treatment.

Prurigo nodularis: A Phase 2 study published in the New England Journal of Medicine (NEJM) was also published (Ruzicka T et al. 2017), 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 nearly 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.

1. Dillon SR et al (2004) Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nature Immunology 5: 752-760.
2. Ferretti E et al.(2015) The interleukin (IL)-31/IL-31R axis contributes to tumor growth in human follicular lymphoma. Leukemia 29: 958-967.
3. Ferretti E et al. (2017) The IL-31/IL-31 receptor axis: general features and role in tumor microenvironment
   .J Leukoc Biole 102:711-717.
4. Ginaldi L et al.(2015) Increased levels of interleukin 31 (IL-31) in osteoporosis. BMC Immunol 16:60.
5. Gonzales AJ et al (2013) Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis. Vet Dermatol 24:48-53.
6. Hawro T et al (2014) Interleukin-31 does not induce immediate itch in atopic dermatitis patients and healthy controls after skin challenge. Allergy 69:113-117.
7. Hermanns HM (2015) Oncostatin M and interleukin-31: Cytokines, receptors, signal transduction and physiology. Cytokine Growth Factor Rev 26:545-558.
8. Huang HT et al (2016) The association of interleukin-31 polymorphisms with interleukin-31 serum levels and risk of systemic lupus erythematosus. Rheumatol Int 36:799-805.
9. Kasraie S et al (2013) Interleukin (IL)-31 activates signal transducer and activator of transcription (STAT)-1, STAT-5 and extracellular signal-regulated kinase 1/2 and down-regulated IL-12p40 production in activated human macrophages. Allergy 68(:739-747.
10. Kasraie S et al (2011) Functional effects of interleukin 31 in human primary keratinocytes. Allergy 66:845-852.
11. Ko MJ et al (2014) Interleukin-31 is associated with uremic pruritus in patients receiving hemodialysis. J Am Acad Dermatol 71:1151-1159.
12. Lai T et al (2016) Interleukin-31 expression and relation to disease severity in human asthma. Sci Rep 6:22835.
13. Lange M et al (2017) Interleukin-31 Polymorphisms and Serum IL-31 Level in Patients with Mastocytosis: Correlation with Clinical Presentation and Pruritus. Acta Derm Venereol 97:47-53.
14. Maier E et al(2015) Prerequisites for Functional Interleukin 31 Signaling and Its Feedback Regulation by Suppressor of Cytokine Signaling 3 (SOCS3). J Biol Chem 290:24747-14759.
15. Moaaz M et al(2016) Stem Cell Factor and Interleukin-31 Expression: Association with IgE among Egyptian Patients with Atopic and Nonatopic Bronchial Asthma. Immunol Invest 45:87-106.
16. Musolino C et al. (2015) Possible Role of Interleukin-31/33 Axis in Imatinib Mesylate-Associated Skin Toxicity. Turk J Haematol 32:168-171.
17. Rabenhorst A et al (2014) Interleukin-31: a novel diagnostic marker of allergic diseases. Curr Allergy Asthma Rep 14:423.
18. Ruzicka T et al. (2017) Anti-Interleukin-31 Receptor A Antibody for Atopic Dermatitis N Engl J Med 376:826-835.
19. Zeng X et al (2016) Clinical Significance of Serum Interleukin-31 and Interleukin-33 Levels in Patients of Endometrial Cancer: A Case Control Study. Dis markers 2016: 9262919.
20. Zhang Q et al (2008) Structures and biological functions of IL-31 and IL-31 receptors. Cytokines & Growth Factor Reviews 19: 347-356.