Epub ahead of print April 13, 2017 - doi:10.1189/jlb.3MR0117-033R
Review
The IL-31/IL-31 receptor axis: general features and role in tumor microenvironment Elisa Ferretti,* Anna Corcione,*,1 and Vito Pistoia†,1,2 *Laboratory of Oncology, Istituto Giannina Gaslini, Genova, Italy; and †Immunology Area, Ospedale Pediatrico Bambino Gesu, ` Roma, Italy RECEIVED JANUARY 24, 2017; REVISED MARCH 15, 2017; ACCEPTED MARCH 15, 2017. DOI: 10.1189/jlb.3MR0117-033R
ABSTRACT IL-31 is a recently identified cytokine with a well-defined role in the pathogenesis of pruritus. IL-31, whose production is induced by IL-4 and IL-33, binds a heterodimeric receptor (R) composed of the exclusive IL-31RA chain and the shared oncostatin M R. Signaling through the IL-31R involves the MAPK, PI3K/AKT and Jak/STAT pathways. Different variants and isoforms of IL-31RA with different signaling activities have been identified. IL-31 is produced predominantly by circulating Th2 lymphocytes and skin-homing CLA+CD45RO+ T cells. Studies in humans have demonstrated a pathogenic role for IL-31 in atopic dermatitis and allergic asthma. The first demonstration of the involvement of the IL-31/IL-31R axis in cancer came from studies in patients with mycosis fungoides/Sezary ´ syndrome, the most frequent, cutaneous T cell lymphoma. Tumor cells were shown to produce IL-31, whose serum levels correlated with pruritus intensity. Follicular lymphoma (FL) B cells and their counterparts—germinal center B cells—produced IL-31 and expressed IL-31R, which signaled in the former, but not the latter, cells. IL-31 released in association with microvesicles promoted tumor growth through autocrine/paracrine loops. Malignant mast cells from patients with mastocytosis or Philadelphia-negative myeloproliferative disorder produced IL-31, which contributed to pruritus pathogenesis. Finally, patients with endometrial carcinoma displayed high serum levels of IL-31 and IL-33, which may represent promising disease biomarkers. Targeting strategies for the IL-31/IL-31R axis have been developed, including the CIMM331 humanized anti-human IL-31RA antibody recently tested in a phase I/Ib study. J. Leukoc. Biol. 102: 000–000; 2017.
Introduction IL-31 was discovered almost 15 years ago, after the identification of the IL-31RA chain by 3 different groups [1–3]. IL-31 is a member of the family of the gp130/IL6 cytokines; most of which are 4-helix (named A–D) bundle cytokines with 3 different Abbreviations: AD = atopic dermatitis, CLA = cutaneous lymphocyte Ag, CTCL = cutaneous T cell lymphoma, EC = endometrial carcinoma, FL = follicular lymphoma, GC = germinal center, gp = glycoprotein, MF = mycosis fungoides, MV = microvesicle, OSM = oncostatin M, R = receptor, SS = Sezary ´ syndrome
receptor-binding sites, referred to as 1–3 [1, 4]. In addition, most gp130/IL-6 cytokines have long-chain (20–30 amino acids) helices. IL-31 is different because it possesses 2 long (A and D, 25–28 amino acids) and 2 short (B and C, 10–16 amino acids) helices [1]. The gene encoding human IL-31 is located on chromosome band 12q24.31, and the mouse ortholog in a synthetic region of chromosome 5; human IL-31 protein is 31% homolog to mouse IL-31. Nonetheless, there is no species cross-reactivity between human and mouse IL-31 [4]. IL-31 binds a heterodimeric R, composed of exclusive IL-31RA, and the shared OSMR [1, 4, 5]. The human IL-31RA protein, previously known as gp130-like, shows 28% amino acid identity with gp130, the common receptor component for IL-6 family cytokines [4]. The gene encoding IL-31RA maps on chromosome band 5q11.2, which is 24 kb downstream of the gp130 gene, suggesting that the 2 genes may have evolved by duplication of an ancestral gene [4]. The heterodimerization of IL-31RA with OSMR is necessary to generate the high-affinity IL-31R. OSMR, in addition to contributing to the formation of IL-31R, heterodimerizes with gp130 or with the leukemia-inhibitory factor R to form 2 alternative OSMRs [1, 4, 5]. Since its first identification, it was apparent that IL-31 had a role in the pathogenesis of some allergic disorders, especially atopic dermatitis [1, 5–10]. Thereafter, IL-31 was considered a Th2related cytokine. Here, we will review the general features of the IL-31/IL-31R system and then focus on its involvement in cancer.
IL-31 CELLULAR SOURCES IL-31 mRNA expression has been detected in a variety of tissues, including skin, lung, small intestine, and the nervous system [4]. Low levels of IL-31 mRNA have also been found in testis, human bone marrow, thymus, spleen, kidney, and skeletal muscle [4]. Th2 cells from peripheral blood and skin-homing CD45RO+CLA+ T cells are the major cellular sources of IL-31 [7]. Additional sources are CD8+ T cells, mast cells, monocytes/macrophages, GC B cells, immature and mature dendritic cells, epidermal 1. These authors contributed equally to this work. 2. Correspondence: Immunology Area, Ospedale Pediatrico Bambino Gesu, ` Viale San Paolo, 15 – 00146 Roma, Italy. E-mail: [email protected]
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keratinocytes, and dermal fibroblasts [1, 5, 11–13]. Most of those cell types require activation to express IL-31 mRNA and protein. IL-31-inducing stimuli include staphylococcal enterotoxin B, which mimics the penetration of broken skin by Staphylococcus Aureus [14], as well as ultraviolet B rays or H2O2, which mimics the inflammatory reaction with consequent release of reactive oxygen species [15]. Additional stimuli that trigger IL-31 expression in mast cells are IgE and human b-defensins and cathelicidin LL37 antimicrobial peptides [12]. Those latter molecules are secreted by monocytes and keratinocytes after stimulation with bacteria or inflammatory cytokines (e.g., IFN-g) [12]. Allergen-stimulated polyclonal or clonal Th2 cells produced IL-31, and IL-4 receptor signaling was essential to induce IL-31 expression [16]. Not only IL-4 but also the Th2 cytokine IL-33 induced T cell expression of IL-31 [16, 17]. Notably, in those experiments, Th1 clones, which did not express IL-31 per se, transiently produced the cytokine upon incubation with IL-4 [16]. Those results demonstrate that IL-31 is not a classic Th2 cytokine but, rather, an IL-4–dependent molecule that can be expressed by different cell types, including normal human bronchial epithelial cells [18], in the course of an allergic disorder. Finally, triggering of the H4 histamine receptor on the surface of CD4+ T cells with the 4-methyl-histamine agonist up-regulated IL-31 expression, further linking this cytokine to allergic inflammation [19].
mouse and humans and is of particular relevance in view of the pruritogenic activity of IL-31 [25]. A number of splice variants of the IL-31RA gene have been identified, whose functional meanings are not yet fully understood. Various laboratories, including our own (see below), have reported the lack of IL-31 signaling, in spite of expression of IL-31RA and OSMR on target cell surface, pointing to the existence of a truncated dominant-negative IL-31RA isoform [2]. Finally, an IL-31RA soluble isoform that may act as an IL-31 antagonist has been identified [4]. IL-31 signaling has been investigated in different cellular models, with some variation in the different experimental conditions tested. Three major signaling pathways have been identified, namely 1) MAPK, 2) PI3K/AKT, and 3) Jak/STAT [5, 20] (Fig. 1). As for the first pathway, IL-31RA or OSMR alone cannot activate ERK1/2, and it is hypothesized that IL-31 binding to IL-31RA recruits OSMR, which is the only chain capable of activating MAPK. A similar model applies to the PI3K/AKT pathway, whereby binding of IL-31 to its heterodimeric receptor induces mild phosphorylation of PI3K and strong phosphorylation of AKT. However, recruitment of SHP2 and the adaptor protein Shc is operated exclusively by OSMR. Finally, IL-31 activates after binding to IL-31R Jak 1 and Jak 2, which stimulate phosphorylation of STAT3, STAT5, and to a lesser extent, STAT1 [5, 20].
IL-31 R EXPRESSION AND SIGNALING The IL-31R is a heterodimer composed of IL-31RA and OSMR, but IL31 first binds IL-31RA through its binding site 2 and then OSMR through binding site 3 [2, 20]. The initial step whereby IL-31 binds IL-31RA likely induces a conformational change in IL-31, allowing subsequent OSMR binding [2, 20]. The tissue and cellular expression of OSMR is not discussed here because of its ubiquitous distribution. IL-31RA mRNA is expressed in the trachea, skeletal muscle, thymus, peripheral blood lymphocytes, placenta, bone marrow, thyroid, testis, brain, and skin [1, 3]. The IL-31RA transcript and protein are found in eosinophils, mast cells, dendritic cells, GC B cells, keratinocytes, pulmonary macrophages, human dermal microvascular endothelial cells, primary cells of bronchial epithelia, colonic subepithelial myofibroblasts, neurons of the dorsal root ganglia, and numerous cell lines derived from transformed cells (osteosarcomas, glioblastomas, melanomas, and myelomonocytic leukemias) [1–4, 13, 21]. Various stimuli have been reported to induce IL-31RA expression in the above cell types. The two major triggers are IFN-g and TGF-b; the former cytokine promotes IL-31RA expression in pulmonary macrophages, monocytes, dendritic cells, keratinocytes, and human microvascular endothelial cells [22, 23], whereas TGF-b stimulates primary cells of bronchial epithelia [21]. In mast cells, binding of anti-IgE to FceRI triggers tyrosine phosphorylation [24]; because mast cells express IL-31 under the same conditions, it is conceivable that autocrine/ paracrine interactions between the cytokine and its receptor contribute to mast cell activation. IL-31RA expression in the neuron of the dorsal root ganglia has been demonstrated in 2
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Figure 1. IL-31, upon binding to its heterodimeric receptor composed of the IL-31RA and the OSMR chains, induces phosphorylation of Jak1/2, which in turn, triggers phosphorylation of STAT1/3/5 or PI3K/AKT. These pathways contribute to skin inflammation, asthma and allergic rhinitis, and gut inflammation.
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MOUSE MODELS FOR FUNCTIONAL STUDIES OF THE IL-31/IL-31R AXIS The first model was developed by Dillon et al. [1], who generated IL-31 transgenic mice in which the cytokine was expressed ubiquitously under the control of the EF1a promoter or specifically in lymphocytes using the Em-lcl promoter. All mice showed pathology confined to the skin and consisting of alopecia and pruritus, with histologic features of hyperkeratosis, acanthosis, and infiltration of inflammatory cells, including mast cells. That phenotype is quite similar to and strongly reminiscent of that observed in human atopic dermatitis (see below). The pruritogenic activity of IL-31 has also been demonstrated by intradermal injection of IL-31, causing a long-lasting scratching, independent of lymphocytes [1, 25]. Accordingly, IL-31RAdeficient mice did not develop either pruritus or alopecia or any immunologic abnormality [1, 25]. However, those mice displayed decreased absolute numbers and cycling status of immature subsets of hematopoietic progenitors in bone marrow and spleen in the absence of any change in circulating red blood cells and platelets [26]. In contrast, the latter cells types were significantly, although not dramatically, reduced in OSMR-deficient mice [27]. The role of the IL-31/IL-31R axis in mouse models of Th2mediated inflammation is controversial. The first study was carried out in a model of Ag-induced airway hyperresponsiveness and showed increased IL-31 expression in lung tissue and lung infiltrates, lending support to a pathogenic role for the cytokine [28]. More recently, it was proposed that IL-31 signaling is necessary to dampen Th2 responses through IL-31RA-deficient mice challenged with Schistosoma mansoni eggs or the gastrointestinal helminth Trichuris muris [29]. Those mice showed an exacerbation of pulmonary and intestinal inflammation, respectively, together with enhanced Th2 and normal Th1 responses [29]. In contrast, in another study in which IL-31 was neutralized in vivo with a specific Ab, no overproduction of Th2 cytokines was observed [30]. Furthermore, IL-31RA-deficient mice were hypersensitive to OSM intranasal administration, suggesting that, in the absence of IL-31RA, OSMR can heterodimerize with gp130 and signal upon binding to OSM [30]. In essence, those discrepant results, which may be related to the different experimental models employed, prompt further investigation to clarify such a vexing issue.
THE IL-31/IL-31R AXIS AND INFLAMMATORY DISEASES Consistent with the results obtained in preclinical studies, IL-31 has been linked to human AD, a chronic, Th2-dependent skin disease characterized by cutaneous lesions with thickening (a process termed lichenification), severe pruritus associated with excoriations and increased proneness to cutaneous infections [6, 8, 31]. IL-31 was overexpressed in skin biopsies from patients with pruritogenic AD and, at higher levels, with prurigo nodularis [6, 8, 31]. IL-31 fuels skin inflammation by inducing keratinocytes to release chemokines, such as CCL1, CCL17, and CCL22, which recruit IL-31–producing T cells to the skin, thus perpetuating the vicious cycle [32].
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IL-31 and tumor microenvironment
Expression of IL-31 was recently investigated in serum, bronchoalveolar lavage fluid, and bronchial tissue from patients with allergic asthma vs. controls [33]. The former individuals displayed higher IL-31 serum and bronchoalveolar lavage fluid levels than the latter did [33]. Patients with severe asthma showed higher expression of IL-31 and IL-31R in bronchial tissue compared with those with mild disease or with controls. High IL-31 serum levels in asthmatic patients positively correlated with those ofTh2 cytokines (IL-5, IL-13, and thymic stromal lymphopoietin) [33]. Those results demonstrate a role for IL-31 in asthma pathogenesis that must be clarified by future studies. The ability of IL-31 to activate and attract colon cancer– derived, intestinal epithelial cell lines and to induce chemokine and matrix metalloprotease production by human colonic, subepithelial myofibroblasts points to a potential role for the IL-31/IL-31 R axis in inflammatory bowel disease, which, however, has not yet been investigated in patients [34, 35]. Finally, primary cutaneous amyloidosis, an itchy skin disorder characterized by focal deposition of amyloids in the skin dermal papillae that affects individuals from Brazil, Britain, South Africa, and Thailand, is a genetic disorder with mutations in the OSMRor IL-31RA–encoding genes [36].
THE IL-31/IL-31R AXIS AND CANCER The first studies of the involvement of the IL-31/IL-31R axis in cancer were incited by the analogies between MF and AD. MF and SS are the most common types of CTCL [37]. Both MF and SS are malignant, clonal proliferations of Th2-biased CD4 +CD45RO+ CLA + T lymphocytes that, in the case of MF, traffic preferentially to the skin, whereas, in SS, may also be detected in the circulating compartment. Similar to AD, CTCLs display eosinophilia and high serum levels of IgE and Th-2–related cytokines [37]. Clinical manifestations of CTCL include erythematous patches, plaques, pruritus, erythroderma, and, with disease progression, skin tumors, lymphadenopathy, and visceral involvement [37]. Increased IL-31 serum levels were detected in patients with CTCL, compared with healthy controls, and in patients with advanced-stage CTCL, compared with those with early stage disease [38]. High concentrations of serum IL-31 correlated with pruritus intensity and with serum and tissue expression of the chemokine CCL18. Malignant CD4+ T cells from CTCL can be identified by flow cytometry because of the loss of T cell markers, such as CD2, CD3, CD5, CD7, and CD26, and the clonal expression of a dominant T cell receptor Vb [39]. With either approach to selecting tumor cells, the latter cells were the predominant source of IL-31. Accordingly, after multimodality treatment and resolution of pruritus, the proportion of malignant cells expressing IL-31 strongly decreased along with the serum levels of the cytokine [38, 40]. Those studies paved the way to the investigation of the role of the IL-31/IL-31R axis in FL, a tumor originating from the GC, which represents the second most-frequent type of lymphoma in the general population [13]. FL cells isolated from invaded lymph nodes expressed both chains of the IL-31R, which, upon incubation with IL-31, were signaled by phosphorylating Erk1/2,
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STAT1, STAT3, and Akt. Furthermore, FL cells exposed to IL-31 were stimulated to proliferate. GC B cells, which represent the normal counterparts of FL cells, expressed both chains of the IL-31R, but did not phosphorylate Erk1/2, STAT1, STAT3, or Akt after exposure to IL-31. That apparent “gain of function” by IL-31R in FL cells compared with GC B cells was found to depend, at least in part, on differential expression of 2 well-characterized IL-31RA isoforms, the long one (745 aa), which has been associated with signaling activity, and the short one (560 aa), which is considered dominant negative. Thus, FL cells expressed the long IL-31RA isoform, whereas GC B cells expressed the short one [13]. Because IL-31RA protein can be translated from 5 IL-31RA mRNA variants, we investigated the expression of such variants and the deduced isoforms in FL and GC B cells. FL expressed IL-31RA proteins with complete extracellular regions and complete or incomplete cytoplasmic regions (variants 1, 3, 4, and 5), whereas GC B cells expressed IL-31RA protein lacking aa 1–21 but which had complete cytoplasmic regions (variant 2). Those differences may contribute further to the failure of GC B cells to signal upon incubation with IL-31 [13]. IL-31 mRNA and protein expression was detected in FL and GC B cells at similar levels, but immunohistochemical analyses revealed a more abundant and diffuse expression of the cytokine in FL than in reactive lymph nodes [13]. FL grows slowly, and tumor-infiltrated lymph nodes retain a partial follicular structure for a long time before being disrupted by neoplastic cells in the late phase of the disease. Furthermore, the FL microenvironment is enriched with IL-4, the best inducer of IL-31 expression [41]. It was thought, therefore, that non–B cells present in FL lymph nodes might contribute significantly to IL-31 expression. That was indeed the case because CD20+ B cells and, to a lesser extent, CD4+ T cells, and CD68+ macrophages were found to express IL-31 [13]. The finding that FL cells expressed both IL-31 and IL-31R, which was fully competent for signaling, pointed to potential autocrine loops of neoplastic cell survival and growth. In addition, the availability in the FL microenvironment of IL-31 produced by different types of non–T cells suggested the existence of paracrine loops that potentially modulate tumor cell growth [13]. However, IL-31 protein was not secreted in the supernatant of FL or GC B cells, even after stimulation of the latter cells with the CD40 ligand and IL-4. Western blot experiments surprisingly demonstrated that IL-31 was expressed at higher levels in the membrane than it was in the cytosolic fractions of FL and GC B cells [13]. Thus, we reasoned that the cytokine could be released in culture supernatants in association with MVs, which are surface membrane–derived, extracellular vesicles. Indeed, FL and GC B cell-derived MVs contained IL-31 and, upon incubation with FL cells, induced STAT1 phosphorylation in the latter cells [13]. Finally, experiments on lymph node tissue sections from patients with FL and different histologic gradings showed that the proportion of IL-31+ and IL-31RA+ cells increased progressively in high-grade tumors in parallel with the effacement of the lymph node architecture operated by FL cells [13]. Taken together, those findings supported the conclusion that, in the FL microenvironment, cellto-cell transfer of IL-31 through MVs was involved in autocrine/ paracrine loops promoting tumor growth [13]. 4
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Mastocytosis is a clonal disorder characterized by expansion of mast cells that infiltrate tissues, in particular skin and bone marrow [42]. Various subtypes of mastocytosis, ranging from benign to aggressive, are known. The former include cutaneous mastocytosis and indolent systemic mastocytosis; the latter comprise aggressive systemic mastocytosis and mast cell leukemia [42]. Increased serum levels of IL-31 have been detected in patients with mastocytosis compared with healthy controls [43]. In addition, patients with advanced disease exhibited significantly higher IL-31 levels than that of patients with nonadvanced disease. Immunohistochemical analyses of skin and bone marrow biopsies allowed the demonstration of tryptase-positive mast cells as a major source of IL-31 [43]. A recent study addressed the analysis of 3 IL-31 gene polymorphisms (IL-31–1066 G/A, IL-31–2057G/A, and IL-31 IVS2+12AG) in a large cohort of patients with mastocytosis and investigated the correlations between the incidence of such polymorphisms with serum levels of IL-31 [44]. The frequency of the IL-31 IVS2+12AA genotype and IVS2+12A allele was higher than in the control group and was associated with increased risk of mastocytosis development. The IL-31–2057AA genotype was found to be associated with an increased risk of mastocytosis in adult patients, but not in children, who suffer from a localized and more benign form of disease. In contrast, the IVS2+12AG genotype was linked with a decreased risk of mastocytosis occurrence in both children and adults. Finally, no correlation was identified between any IL-31 gene polymorphism studied and IL-31 serum levels [44]. Mast cells belonging to the malignant clone in Philadelphianegative myeloproliferative disorder were found to release large amounts of pruritogenic factors, including IL-31 [11]. The presence of pruritus correlated with high proportions of IL-31+ mast cells generated from CD34+ progenitor cells and high plasma levels of the cytokine [11]. Few studies on the IL-31/IL-31R in solid tumors have been published. A negative correlation was found between serum IL-31 levels at diagnosis and time to progression in patients with non–small cell lung cancer [45]. In another study, no differences were detected in serum IL-31 levels among patients with hepatocellular carcinoma, chronic hepatitis B, and healthy controls [46]. EC is the second most common, female cancer occurring during perimenopause and menopause. Endometrial inflammation is an important risk factor for EC [47]. Serum levels of IL-31 and IL-33 were found to be significantly elevated in patients with EC compared with healthy controls and correlated with clinical characteristics, including tumor stages, depth of invasion, and lymph node or distant metastases [48]. Sensitivity and specificity of serum IL-31 and IL-33 was superior to that of tumor markers, supporting the hypothesis that both cytokines may represent potential tumor biomarkers. The link between IL-31 and IL-33 is intriguing because IL-33, a Th2 cytokine that can induce IL-31 expression, is up-regulated in colorectal cancer and tumor epithelial cells [49] and appears to have a crucial role in the development of myeloproliferative disorders [50]. On the other hand, IL-33 can restrain tumor growth in certain experimental conditions by activating NK cells and CD8+
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IL-31 and tumor microenvironment
Figure 2. The contribution of soluble (s) or microvesicle (MV)-associated IL-31 to the pathogenesis of various malignancies.
T cells [51]. An interesting case report has been published, regarding a patient with bronchoalveolar carcinoma who developed skin rash, xerosis, and pruritus during treatment with various EGFR tyrosine kinase inhibitors [52]. Serum IL-31 and IL-33 were elevated during treatment, and it was proposed that tyrosine kinase inhibitors caused keratinocyte injury, subsequent release of IL-33, and binding of the cytokine to its receptors on mast cells, leading to the secretion of different pruritogenic factors, including IL-31 [52]. Further studies are needed to gain insight into the relations between IL-31 and IL-33 in cancer. Figure 2 summarizes the involvement of the IL-31/IL-31R axis in the malignancies discussed above.
TARGETING OF THE IL-31/IL-31RA AXIS Various strategies have been adopted to generate inhibitors of the IL-31/IL-31RA axis. CIMM331 is a humanized anti-human IL-31 RA Ab that binds to the latter receptor chain and inhibits IL-31 signaling [53]. A double-blind, placebo-controlled, phase I/Ib study was recently carried out, in which healthy volunteers and patients with AD received a single s.c. dose of the Ab. That schedule was well tolerated in healthy individuals and patients with AD and decreased pruritus, sleep disturbance, and topical corticosteroid use in the latter group [53]. A potent IL-31 antagonist has been generated by fusing the external portion of OSMR and IL-31RA. That fusion protein inhibited the binding of IL-31 to IL-31R and prevented signaling in brain-derived cell lines and primary keratinocytes [54]. Finally, administration of vorinostat, a histone deacetylase inhibitor, to patients with CTCL mitigated pruritus and reduced the proportions of IL-31–expressing T cells [54]. Because at least
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a one-half of CD4+CD26+ malignant T cells express the chemokine receptor CCR4, targeting such cells with the anti-CCR4 Ab mogamulizumab strongly reduced the number of IL-31– producing tumor cells and decreased patient pruritus [55].
CLOSING REMARKS IL-31 is one of the most recently discovered cytokines with a clearly defined role in the pathogenesis of pruritus in patients with AD and prurigo nodularis. Studies performed in patients with cancer have shown a role for the IL-31/IL-31RA axis, especially in tumors of hematopoietic origin, i.e., CTLC, FL, mastocytosis, and Philadelphia-negative myeloproliferative disorder. IL-31 produced by both malignant and reactive cells causes pruritus and, in the case of FL, supports tumor growth through autocrine and paracrine loops. Strategies targeting the IL-31/ IL-31RA system are being developed. Further studies will establish whether such strategies will be helpful not only in allergic dermatologic disorders but also in cancer.
AUTHORSHIP E.F, A.C., and V.P. contributed equally to manuscript organization and writing.
ACKNOWLEDGMENTS The studies reported herein were supported by Associazione Italiana per la Ricerca sul Cancro Grants 17273 and 13003 to V.P.
DISCLOSURE
The authors declare no conflicts of interest.
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50. Mager, L. F., Riether, C., Sch¨urch, C. M., Banz, Y., Wasmer, M. H., Stuber, R., Theocharides, A. P., Li, X., Xia, Y., Saito, H., Nakae, S., Baerlocher, G. M., Manz, M. G., McCoy, K. D., Macpherson, A. J., Ochsenbein, A. F., Beutler, B., Krebs, P. (2015) IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms. J. Clin. Invest. 125, 2579–2591. 51. Molofsky, A. B., Savage, A. K., Locksley, R. M. (2015) Interleukin-33 in tissue homeostasis, injury, and inflammation. Immunity 42, 1005–1019. 52. Gangemi, S., Franchina, T., Minciullo, P. L., Profita, M., Zangh`ı, M., David, A., Kennez, I., Adamo, V. (2013) IL-33/IL-31 axis: a new pathological mechanisms for EGFR tyrosine kinase inhibitors-associated skin toxicity. J. Cell. Biochem. 114, 2673–2676. 53. Nemoto, O., Furue, M., Nakagawa, H., Shiramoto, M., Hanada, R., Matsuki, S., Imayama, S., Kato, M., Hasebe, I., Taira, K., Yamamoto, M., Mihara, R., Kabashima, K., Ruzicka, T., Hanifin, J., Kumagai, Y. (2016) The first trial of CIM331, a humanized antihuman interleukin-31 receptor A antibody, in healthy volunteers and patients with atopic dermatitis to evaluate safety, tolerability and pharmacokinetics of a single dose in a randomized, double-blind, placebo-controlled study. Br. J. Dermatol. 174, 296–304. 54. Venereau, E., Diveu, C., Grimaud, L., Ravon, E., Froger, J., Preisser, L., Danger, Y., Maillasson, M., Garrigue-Antar, L., Jacques, Y., Chevalier, S., Gascan, H. (2010) Definition and characterization of an inhibitor for interleukin-31. J. Biol. Chem. 285, 14955–14963. 55. Cedeno-Laurent, F., Singer, E. M., Wysocka, M., Benoit, B. M., Vittorio, C. C., Kim, E. J., Yosipovitch, G., Rook, A. H. (2015) Improved pruritus correlates with lower levels of IL-31 in CTCL patients under different therapeutic modalities. Clin. Immunol. 158, 1–7.
KEY WORDS: cytokine allergy cancer growth •
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The IL-31/IL-31 receptor axis: general features and role in tumor microenvironment Elisa Ferretti, Anna Corcione and Vito Pistoia J Leukoc Biol published online April 13, 2017 Access the most recent version at doi:10.1189/jlb.3MR0117-033R
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Review
The IL-31/IL-31 receptor axis: general features and role in tumor microenvironment Elisa Ferretti,* Anna Corcione,*,1 and Vito Pistoia†,1,2 *Laboratory of Oncology, Istituto Giannina Gaslini, Genova, Italy; and †Immunology Area, Ospedale Pediatrico Bambino Gesu, ` Roma, Italy RECEIVED JANUARY 24, 2017; REVISED MARCH 15, 2017; ACCEPTED MARCH 15, 2017. DOI: 10.1189/jlb.3MR0117-033R
ABSTRACT IL-31 is a recently identified cytokine with a well-defined role in the pathogenesis of pruritus. IL-31, whose production is induced by IL-4 and IL-33, binds a heterodimeric receptor (R) composed of the exclusive IL-31RA chain and the shared oncostatin M R. Signaling through the IL-31R involves the MAPK, PI3K/AKT and Jak/STAT pathways. Different variants and isoforms of IL-31RA with different signaling activities have been identified. IL-31 is produced predominantly by circulating Th2 lymphocytes and skin-homing CLA+CD45RO+ T cells. Studies in humans have demonstrated a pathogenic role for IL-31 in atopic dermatitis and allergic asthma. The first demonstration of the involvement of the IL-31/IL-31R axis in cancer came from studies in patients with mycosis fungoides/Sezary ´ syndrome, the most frequent, cutaneous T cell lymphoma. Tumor cells were shown to produce IL-31, whose serum levels correlated with pruritus intensity. Follicular lymphoma (FL) B cells and their counterparts—germinal center B cells—produced IL-31 and expressed IL-31R, which signaled in the former, but not the latter, cells. IL-31 released in association with microvesicles promoted tumor growth through autocrine/paracrine loops. Malignant mast cells from patients with mastocytosis or Philadelphia-negative myeloproliferative disorder produced IL-31, which contributed to pruritus pathogenesis. Finally, patients with endometrial carcinoma displayed high serum levels of IL-31 and IL-33, which may represent promising disease biomarkers. Targeting strategies for the IL-31/IL-31R axis have been developed, including the CIMM331 humanized anti-human IL-31RA antibody recently tested in a phase I/Ib study. J. Leukoc. Biol. 102: 000–000; 2017.
Introduction IL-31 was discovered almost 15 years ago, after the identification of the IL-31RA chain by 3 different groups [1–3]. IL-31 is a member of the family of the gp130/IL6 cytokines; most of which are 4-helix (named A–D) bundle cytokines with 3 different Abbreviations: AD = atopic dermatitis, CLA = cutaneous lymphocyte Ag, CTCL = cutaneous T cell lymphoma, EC = endometrial carcinoma, FL = follicular lymphoma, GC = germinal center, gp = glycoprotein, MF = mycosis fungoides, MV = microvesicle, OSM = oncostatin M, R = receptor, SS = Sezary ´ syndrome
receptor-binding sites, referred to as 1–3 [1, 4]. In addition, most gp130/IL-6 cytokines have long-chain (20–30 amino acids) helices. IL-31 is different because it possesses 2 long (A and D, 25–28 amino acids) and 2 short (B and C, 10–16 amino acids) helices [1]. The gene encoding human IL-31 is located on chromosome band 12q24.31, and the mouse ortholog in a synthetic region of chromosome 5; human IL-31 protein is 31% homolog to mouse IL-31. Nonetheless, there is no species cross-reactivity between human and mouse IL-31 [4]. IL-31 binds a heterodimeric R, composed of exclusive IL-31RA, and the shared OSMR [1, 4, 5]. The human IL-31RA protein, previously known as gp130-like, shows 28% amino acid identity with gp130, the common receptor component for IL-6 family cytokines [4]. The gene encoding IL-31RA maps on chromosome band 5q11.2, which is 24 kb downstream of the gp130 gene, suggesting that the 2 genes may have evolved by duplication of an ancestral gene [4]. The heterodimerization of IL-31RA with OSMR is necessary to generate the high-affinity IL-31R. OSMR, in addition to contributing to the formation of IL-31R, heterodimerizes with gp130 or with the leukemia-inhibitory factor R to form 2 alternative OSMRs [1, 4, 5]. Since its first identification, it was apparent that IL-31 had a role in the pathogenesis of some allergic disorders, especially atopic dermatitis [1, 5–10]. Thereafter, IL-31 was considered a Th2related cytokine. Here, we will review the general features of the IL-31/IL-31R system and then focus on its involvement in cancer.
IL-31 CELLULAR SOURCES IL-31 mRNA expression has been detected in a variety of tissues, including skin, lung, small intestine, and the nervous system [4]. Low levels of IL-31 mRNA have also been found in testis, human bone marrow, thymus, spleen, kidney, and skeletal muscle [4]. Th2 cells from peripheral blood and skin-homing CD45RO+CLA+ T cells are the major cellular sources of IL-31 [7]. Additional sources are CD8+ T cells, mast cells, monocytes/macrophages, GC B cells, immature and mature dendritic cells, epidermal 1. These authors contributed equally to this work. 2. Correspondence: Immunology Area, Ospedale Pediatrico Bambino Gesu, ` Viale San Paolo, 15 – 00146 Roma, Italy. E-mail: [email protected]
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keratinocytes, and dermal fibroblasts [1, 5, 11–13]. Most of those cell types require activation to express IL-31 mRNA and protein. IL-31-inducing stimuli include staphylococcal enterotoxin B, which mimics the penetration of broken skin by Staphylococcus Aureus [14], as well as ultraviolet B rays or H2O2, which mimics the inflammatory reaction with consequent release of reactive oxygen species [15]. Additional stimuli that trigger IL-31 expression in mast cells are IgE and human b-defensins and cathelicidin LL37 antimicrobial peptides [12]. Those latter molecules are secreted by monocytes and keratinocytes after stimulation with bacteria or inflammatory cytokines (e.g., IFN-g) [12]. Allergen-stimulated polyclonal or clonal Th2 cells produced IL-31, and IL-4 receptor signaling was essential to induce IL-31 expression [16]. Not only IL-4 but also the Th2 cytokine IL-33 induced T cell expression of IL-31 [16, 17]. Notably, in those experiments, Th1 clones, which did not express IL-31 per se, transiently produced the cytokine upon incubation with IL-4 [16]. Those results demonstrate that IL-31 is not a classic Th2 cytokine but, rather, an IL-4–dependent molecule that can be expressed by different cell types, including normal human bronchial epithelial cells [18], in the course of an allergic disorder. Finally, triggering of the H4 histamine receptor on the surface of CD4+ T cells with the 4-methyl-histamine agonist up-regulated IL-31 expression, further linking this cytokine to allergic inflammation [19].
mouse and humans and is of particular relevance in view of the pruritogenic activity of IL-31 [25]. A number of splice variants of the IL-31RA gene have been identified, whose functional meanings are not yet fully understood. Various laboratories, including our own (see below), have reported the lack of IL-31 signaling, in spite of expression of IL-31RA and OSMR on target cell surface, pointing to the existence of a truncated dominant-negative IL-31RA isoform [2]. Finally, an IL-31RA soluble isoform that may act as an IL-31 antagonist has been identified [4]. IL-31 signaling has been investigated in different cellular models, with some variation in the different experimental conditions tested. Three major signaling pathways have been identified, namely 1) MAPK, 2) PI3K/AKT, and 3) Jak/STAT [5, 20] (Fig. 1). As for the first pathway, IL-31RA or OSMR alone cannot activate ERK1/2, and it is hypothesized that IL-31 binding to IL-31RA recruits OSMR, which is the only chain capable of activating MAPK. A similar model applies to the PI3K/AKT pathway, whereby binding of IL-31 to its heterodimeric receptor induces mild phosphorylation of PI3K and strong phosphorylation of AKT. However, recruitment of SHP2 and the adaptor protein Shc is operated exclusively by OSMR. Finally, IL-31 activates after binding to IL-31R Jak 1 and Jak 2, which stimulate phosphorylation of STAT3, STAT5, and to a lesser extent, STAT1 [5, 20].
IL-31 R EXPRESSION AND SIGNALING The IL-31R is a heterodimer composed of IL-31RA and OSMR, but IL31 first binds IL-31RA through its binding site 2 and then OSMR through binding site 3 [2, 20]. The initial step whereby IL-31 binds IL-31RA likely induces a conformational change in IL-31, allowing subsequent OSMR binding [2, 20]. The tissue and cellular expression of OSMR is not discussed here because of its ubiquitous distribution. IL-31RA mRNA is expressed in the trachea, skeletal muscle, thymus, peripheral blood lymphocytes, placenta, bone marrow, thyroid, testis, brain, and skin [1, 3]. The IL-31RA transcript and protein are found in eosinophils, mast cells, dendritic cells, GC B cells, keratinocytes, pulmonary macrophages, human dermal microvascular endothelial cells, primary cells of bronchial epithelia, colonic subepithelial myofibroblasts, neurons of the dorsal root ganglia, and numerous cell lines derived from transformed cells (osteosarcomas, glioblastomas, melanomas, and myelomonocytic leukemias) [1–4, 13, 21]. Various stimuli have been reported to induce IL-31RA expression in the above cell types. The two major triggers are IFN-g and TGF-b; the former cytokine promotes IL-31RA expression in pulmonary macrophages, monocytes, dendritic cells, keratinocytes, and human microvascular endothelial cells [22, 23], whereas TGF-b stimulates primary cells of bronchial epithelia [21]. In mast cells, binding of anti-IgE to FceRI triggers tyrosine phosphorylation [24]; because mast cells express IL-31 under the same conditions, it is conceivable that autocrine/ paracrine interactions between the cytokine and its receptor contribute to mast cell activation. IL-31RA expression in the neuron of the dorsal root ganglia has been demonstrated in 2
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Figure 1. IL-31, upon binding to its heterodimeric receptor composed of the IL-31RA and the OSMR chains, induces phosphorylation of Jak1/2, which in turn, triggers phosphorylation of STAT1/3/5 or PI3K/AKT. These pathways contribute to skin inflammation, asthma and allergic rhinitis, and gut inflammation.
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Ferretti et al.
MOUSE MODELS FOR FUNCTIONAL STUDIES OF THE IL-31/IL-31R AXIS The first model was developed by Dillon et al. [1], who generated IL-31 transgenic mice in which the cytokine was expressed ubiquitously under the control of the EF1a promoter or specifically in lymphocytes using the Em-lcl promoter. All mice showed pathology confined to the skin and consisting of alopecia and pruritus, with histologic features of hyperkeratosis, acanthosis, and infiltration of inflammatory cells, including mast cells. That phenotype is quite similar to and strongly reminiscent of that observed in human atopic dermatitis (see below). The pruritogenic activity of IL-31 has also been demonstrated by intradermal injection of IL-31, causing a long-lasting scratching, independent of lymphocytes [1, 25]. Accordingly, IL-31RAdeficient mice did not develop either pruritus or alopecia or any immunologic abnormality [1, 25]. However, those mice displayed decreased absolute numbers and cycling status of immature subsets of hematopoietic progenitors in bone marrow and spleen in the absence of any change in circulating red blood cells and platelets [26]. In contrast, the latter cells types were significantly, although not dramatically, reduced in OSMR-deficient mice [27]. The role of the IL-31/IL-31R axis in mouse models of Th2mediated inflammation is controversial. The first study was carried out in a model of Ag-induced airway hyperresponsiveness and showed increased IL-31 expression in lung tissue and lung infiltrates, lending support to a pathogenic role for the cytokine [28]. More recently, it was proposed that IL-31 signaling is necessary to dampen Th2 responses through IL-31RA-deficient mice challenged with Schistosoma mansoni eggs or the gastrointestinal helminth Trichuris muris [29]. Those mice showed an exacerbation of pulmonary and intestinal inflammation, respectively, together with enhanced Th2 and normal Th1 responses [29]. In contrast, in another study in which IL-31 was neutralized in vivo with a specific Ab, no overproduction of Th2 cytokines was observed [30]. Furthermore, IL-31RA-deficient mice were hypersensitive to OSM intranasal administration, suggesting that, in the absence of IL-31RA, OSMR can heterodimerize with gp130 and signal upon binding to OSM [30]. In essence, those discrepant results, which may be related to the different experimental models employed, prompt further investigation to clarify such a vexing issue.
THE IL-31/IL-31R AXIS AND INFLAMMATORY DISEASES Consistent with the results obtained in preclinical studies, IL-31 has been linked to human AD, a chronic, Th2-dependent skin disease characterized by cutaneous lesions with thickening (a process termed lichenification), severe pruritus associated with excoriations and increased proneness to cutaneous infections [6, 8, 31]. IL-31 was overexpressed in skin biopsies from patients with pruritogenic AD and, at higher levels, with prurigo nodularis [6, 8, 31]. IL-31 fuels skin inflammation by inducing keratinocytes to release chemokines, such as CCL1, CCL17, and CCL22, which recruit IL-31–producing T cells to the skin, thus perpetuating the vicious cycle [32].
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IL-31 and tumor microenvironment
Expression of IL-31 was recently investigated in serum, bronchoalveolar lavage fluid, and bronchial tissue from patients with allergic asthma vs. controls [33]. The former individuals displayed higher IL-31 serum and bronchoalveolar lavage fluid levels than the latter did [33]. Patients with severe asthma showed higher expression of IL-31 and IL-31R in bronchial tissue compared with those with mild disease or with controls. High IL-31 serum levels in asthmatic patients positively correlated with those ofTh2 cytokines (IL-5, IL-13, and thymic stromal lymphopoietin) [33]. Those results demonstrate a role for IL-31 in asthma pathogenesis that must be clarified by future studies. The ability of IL-31 to activate and attract colon cancer– derived, intestinal epithelial cell lines and to induce chemokine and matrix metalloprotease production by human colonic, subepithelial myofibroblasts points to a potential role for the IL-31/IL-31 R axis in inflammatory bowel disease, which, however, has not yet been investigated in patients [34, 35]. Finally, primary cutaneous amyloidosis, an itchy skin disorder characterized by focal deposition of amyloids in the skin dermal papillae that affects individuals from Brazil, Britain, South Africa, and Thailand, is a genetic disorder with mutations in the OSMRor IL-31RA–encoding genes [36].
THE IL-31/IL-31R AXIS AND CANCER The first studies of the involvement of the IL-31/IL-31R axis in cancer were incited by the analogies between MF and AD. MF and SS are the most common types of CTCL [37]. Both MF and SS are malignant, clonal proliferations of Th2-biased CD4 +CD45RO+ CLA + T lymphocytes that, in the case of MF, traffic preferentially to the skin, whereas, in SS, may also be detected in the circulating compartment. Similar to AD, CTCLs display eosinophilia and high serum levels of IgE and Th-2–related cytokines [37]. Clinical manifestations of CTCL include erythematous patches, plaques, pruritus, erythroderma, and, with disease progression, skin tumors, lymphadenopathy, and visceral involvement [37]. Increased IL-31 serum levels were detected in patients with CTCL, compared with healthy controls, and in patients with advanced-stage CTCL, compared with those with early stage disease [38]. High concentrations of serum IL-31 correlated with pruritus intensity and with serum and tissue expression of the chemokine CCL18. Malignant CD4+ T cells from CTCL can be identified by flow cytometry because of the loss of T cell markers, such as CD2, CD3, CD5, CD7, and CD26, and the clonal expression of a dominant T cell receptor Vb [39]. With either approach to selecting tumor cells, the latter cells were the predominant source of IL-31. Accordingly, after multimodality treatment and resolution of pruritus, the proportion of malignant cells expressing IL-31 strongly decreased along with the serum levels of the cytokine [38, 40]. Those studies paved the way to the investigation of the role of the IL-31/IL-31R axis in FL, a tumor originating from the GC, which represents the second most-frequent type of lymphoma in the general population [13]. FL cells isolated from invaded lymph nodes expressed both chains of the IL-31R, which, upon incubation with IL-31, were signaled by phosphorylating Erk1/2,
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STAT1, STAT3, and Akt. Furthermore, FL cells exposed to IL-31 were stimulated to proliferate. GC B cells, which represent the normal counterparts of FL cells, expressed both chains of the IL-31R, but did not phosphorylate Erk1/2, STAT1, STAT3, or Akt after exposure to IL-31. That apparent “gain of function” by IL-31R in FL cells compared with GC B cells was found to depend, at least in part, on differential expression of 2 well-characterized IL-31RA isoforms, the long one (745 aa), which has been associated with signaling activity, and the short one (560 aa), which is considered dominant negative. Thus, FL cells expressed the long IL-31RA isoform, whereas GC B cells expressed the short one [13]. Because IL-31RA protein can be translated from 5 IL-31RA mRNA variants, we investigated the expression of such variants and the deduced isoforms in FL and GC B cells. FL expressed IL-31RA proteins with complete extracellular regions and complete or incomplete cytoplasmic regions (variants 1, 3, 4, and 5), whereas GC B cells expressed IL-31RA protein lacking aa 1–21 but which had complete cytoplasmic regions (variant 2). Those differences may contribute further to the failure of GC B cells to signal upon incubation with IL-31 [13]. IL-31 mRNA and protein expression was detected in FL and GC B cells at similar levels, but immunohistochemical analyses revealed a more abundant and diffuse expression of the cytokine in FL than in reactive lymph nodes [13]. FL grows slowly, and tumor-infiltrated lymph nodes retain a partial follicular structure for a long time before being disrupted by neoplastic cells in the late phase of the disease. Furthermore, the FL microenvironment is enriched with IL-4, the best inducer of IL-31 expression [41]. It was thought, therefore, that non–B cells present in FL lymph nodes might contribute significantly to IL-31 expression. That was indeed the case because CD20+ B cells and, to a lesser extent, CD4+ T cells, and CD68+ macrophages were found to express IL-31 [13]. The finding that FL cells expressed both IL-31 and IL-31R, which was fully competent for signaling, pointed to potential autocrine loops of neoplastic cell survival and growth. In addition, the availability in the FL microenvironment of IL-31 produced by different types of non–T cells suggested the existence of paracrine loops that potentially modulate tumor cell growth [13]. However, IL-31 protein was not secreted in the supernatant of FL or GC B cells, even after stimulation of the latter cells with the CD40 ligand and IL-4. Western blot experiments surprisingly demonstrated that IL-31 was expressed at higher levels in the membrane than it was in the cytosolic fractions of FL and GC B cells [13]. Thus, we reasoned that the cytokine could be released in culture supernatants in association with MVs, which are surface membrane–derived, extracellular vesicles. Indeed, FL and GC B cell-derived MVs contained IL-31 and, upon incubation with FL cells, induced STAT1 phosphorylation in the latter cells [13]. Finally, experiments on lymph node tissue sections from patients with FL and different histologic gradings showed that the proportion of IL-31+ and IL-31RA+ cells increased progressively in high-grade tumors in parallel with the effacement of the lymph node architecture operated by FL cells [13]. Taken together, those findings supported the conclusion that, in the FL microenvironment, cellto-cell transfer of IL-31 through MVs was involved in autocrine/ paracrine loops promoting tumor growth [13]. 4
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Mastocytosis is a clonal disorder characterized by expansion of mast cells that infiltrate tissues, in particular skin and bone marrow [42]. Various subtypes of mastocytosis, ranging from benign to aggressive, are known. The former include cutaneous mastocytosis and indolent systemic mastocytosis; the latter comprise aggressive systemic mastocytosis and mast cell leukemia [42]. Increased serum levels of IL-31 have been detected in patients with mastocytosis compared with healthy controls [43]. In addition, patients with advanced disease exhibited significantly higher IL-31 levels than that of patients with nonadvanced disease. Immunohistochemical analyses of skin and bone marrow biopsies allowed the demonstration of tryptase-positive mast cells as a major source of IL-31 [43]. A recent study addressed the analysis of 3 IL-31 gene polymorphisms (IL-31–1066 G/A, IL-31–2057G/A, and IL-31 IVS2+12AG) in a large cohort of patients with mastocytosis and investigated the correlations between the incidence of such polymorphisms with serum levels of IL-31 [44]. The frequency of the IL-31 IVS2+12AA genotype and IVS2+12A allele was higher than in the control group and was associated with increased risk of mastocytosis development. The IL-31–2057AA genotype was found to be associated with an increased risk of mastocytosis in adult patients, but not in children, who suffer from a localized and more benign form of disease. In contrast, the IVS2+12AG genotype was linked with a decreased risk of mastocytosis occurrence in both children and adults. Finally, no correlation was identified between any IL-31 gene polymorphism studied and IL-31 serum levels [44]. Mast cells belonging to the malignant clone in Philadelphianegative myeloproliferative disorder were found to release large amounts of pruritogenic factors, including IL-31 [11]. The presence of pruritus correlated with high proportions of IL-31+ mast cells generated from CD34+ progenitor cells and high plasma levels of the cytokine [11]. Few studies on the IL-31/IL-31R in solid tumors have been published. A negative correlation was found between serum IL-31 levels at diagnosis and time to progression in patients with non–small cell lung cancer [45]. In another study, no differences were detected in serum IL-31 levels among patients with hepatocellular carcinoma, chronic hepatitis B, and healthy controls [46]. EC is the second most common, female cancer occurring during perimenopause and menopause. Endometrial inflammation is an important risk factor for EC [47]. Serum levels of IL-31 and IL-33 were found to be significantly elevated in patients with EC compared with healthy controls and correlated with clinical characteristics, including tumor stages, depth of invasion, and lymph node or distant metastases [48]. Sensitivity and specificity of serum IL-31 and IL-33 was superior to that of tumor markers, supporting the hypothesis that both cytokines may represent potential tumor biomarkers. The link between IL-31 and IL-33 is intriguing because IL-33, a Th2 cytokine that can induce IL-31 expression, is up-regulated in colorectal cancer and tumor epithelial cells [49] and appears to have a crucial role in the development of myeloproliferative disorders [50]. On the other hand, IL-33 can restrain tumor growth in certain experimental conditions by activating NK cells and CD8+
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IL-31 and tumor microenvironment
Figure 2. The contribution of soluble (s) or microvesicle (MV)-associated IL-31 to the pathogenesis of various malignancies.
T cells [51]. An interesting case report has been published, regarding a patient with bronchoalveolar carcinoma who developed skin rash, xerosis, and pruritus during treatment with various EGFR tyrosine kinase inhibitors [52]. Serum IL-31 and IL-33 were elevated during treatment, and it was proposed that tyrosine kinase inhibitors caused keratinocyte injury, subsequent release of IL-33, and binding of the cytokine to its receptors on mast cells, leading to the secretion of different pruritogenic factors, including IL-31 [52]. Further studies are needed to gain insight into the relations between IL-31 and IL-33 in cancer. Figure 2 summarizes the involvement of the IL-31/IL-31R axis in the malignancies discussed above.
TARGETING OF THE IL-31/IL-31RA AXIS Various strategies have been adopted to generate inhibitors of the IL-31/IL-31RA axis. CIMM331 is a humanized anti-human IL-31 RA Ab that binds to the latter receptor chain and inhibits IL-31 signaling [53]. A double-blind, placebo-controlled, phase I/Ib study was recently carried out, in which healthy volunteers and patients with AD received a single s.c. dose of the Ab. That schedule was well tolerated in healthy individuals and patients with AD and decreased pruritus, sleep disturbance, and topical corticosteroid use in the latter group [53]. A potent IL-31 antagonist has been generated by fusing the external portion of OSMR and IL-31RA. That fusion protein inhibited the binding of IL-31 to IL-31R and prevented signaling in brain-derived cell lines and primary keratinocytes [54]. Finally, administration of vorinostat, a histone deacetylase inhibitor, to patients with CTCL mitigated pruritus and reduced the proportions of IL-31–expressing T cells [54]. Because at least
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a one-half of CD4+CD26+ malignant T cells express the chemokine receptor CCR4, targeting such cells with the anti-CCR4 Ab mogamulizumab strongly reduced the number of IL-31– producing tumor cells and decreased patient pruritus [55].
CLOSING REMARKS IL-31 is one of the most recently discovered cytokines with a clearly defined role in the pathogenesis of pruritus in patients with AD and prurigo nodularis. Studies performed in patients with cancer have shown a role for the IL-31/IL-31RA axis, especially in tumors of hematopoietic origin, i.e., CTLC, FL, mastocytosis, and Philadelphia-negative myeloproliferative disorder. IL-31 produced by both malignant and reactive cells causes pruritus and, in the case of FL, supports tumor growth through autocrine and paracrine loops. Strategies targeting the IL-31/ IL-31RA system are being developed. Further studies will establish whether such strategies will be helpful not only in allergic dermatologic disorders but also in cancer.
AUTHORSHIP E.F, A.C., and V.P. contributed equally to manuscript organization and writing.
ACKNOWLEDGMENTS The studies reported herein were supported by Associazione Italiana per la Ricerca sul Cancro Grants 17273 and 13003 to V.P.
DISCLOSURE
The authors declare no conflicts of interest.
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IL-31 and tumor microenvironment
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KEY WORDS: cytokine allergy cancer growth •
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Volume 102, September 2017 Journal of Leukocyte Biology Downloaded from www.jleukbio.org to IP 128.122.230.148. Journal of Leukocyte Biology Vol., No. , pp:, April, 2017
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The IL-31/IL-31 receptor axis: general features and role in tumor microenvironment Elisa Ferretti, Anna Corcione and Vito Pistoia J Leukoc Biol published online April 13, 2017 Access the most recent version at doi:10.1189/jlb.3MR0117-033R
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