Laboratory of Oncology, Istituto Giannina Gaslini, Genova, Italy; and.
Immunology Area, Ospedale Pediatrico Bambino Gesù, Roma, Italy
J Leukoc Biol. 2017 Sep;102(3):711-717. doi: 10.1189/jlb.3MR0117-033R. Epub 2017 Apr 13.
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 CLACD45RO 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/Sézary 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.
白细胞介素-31（IL-31）是一种新发现的细胞因子，其在瘙痒症的发病机制中具有明确作用。白细胞介素-31 由白细胞介素-4 和白细胞介素-33 诱导产生，与由独特的白细胞介素-31RA 链和共同的肿瘤坏死因子受体组成的异二聚体受体（R）结合。通过白细胞介素-31R 信号转导涉及丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇 3-激酶/蛋白激酶 B（PI3K/AKT）和 Jak/信号转导和转录激活因子（Jak/STAT）途径。已鉴定出具有不同信号转导活性的白细胞介素-31RA 的不同变体和同工型。白细胞介素-31 主要由循环 Th2 淋巴细胞和皮肤归巢的 CD45RO+T 细胞产生。人类研究表明白细胞介素-31 在特应性皮炎和过敏性哮喘中具有致病性作用。IL-31/IL-31R 轴参与癌症的第一个证据来自蕈样真菌病/Sezary 综合征（最常见的皮肤 T 细胞淋巴瘤）患者的研究。研究表明肿瘤细胞产生白细胞介素-31，其血清水平与瘙痒强度相关。滤泡性淋巴瘤（FL）B 细胞及其对应物-生发中心 B 细胞产生白细胞介素-31 并表达白细胞介素-31R，在前一种细胞中信号转导，但在后一种细胞中不信号转导。与微泡一起释放的白细胞介素-31 通过自分泌/旁分泌环促进肿瘤生长。肥大细胞增多症或费城阴性骨髓增生性疾病患者的恶性肥大细胞产生白细胞介素-31，这有助于瘙痒症的发病机制。最后，子宫内膜癌患者显示白细胞介素-31 和白细胞介素-33 的血清水平较高，这可能代表有前途的疾病生物标志物。已经开发了针对白细胞介素-31/白细胞介素-31R 轴的靶向策略，包括最近在 I/ Ib 期研究中测试的 CIMM331 人源化抗人白细胞介素-31RA 抗体。
