BACKGROUND The role of IL-37, an immunosuppressive cytokine, in patients with inflammatory diseases is unclear. OBJECTIVE We sought to explore the expression and pathogenic function of IL-37 in patients with chronic rhinosinusitis (CRS). METHODS Expression levels of IL-37, IL-18 receptor α, IL-1 receptor 8, Mex3 RNA binding family member B (Mex3B), and thymic stromal lymphopoietin (TSLP) in nasal samples were studied by using quantitative RT-PCR, immunohistochemistry, Western blotting, and ELISA. Human nasal epithelial cells (HNECs) and the BEAS-2B cell line were stimulated with various cytokines and Toll-like receptor (TLR) agonists. In some experiments BEAS-2B cells were transfected with Mex3B small interfering RNA or overexpressing lentiviruses. Genes regulated by IL-37b in HNECs were studied by using RNA sequencing analysis. IL-37b function was confirmed in mice in vivo. RESULTS Compared with control subjects, although mRNA and protein expression of IL-37 were upregulated in diseased tissues, especially in nasal epithelial cells, in patients with CRS without nasal polyps or in patients with chronic rhinosinusitis with nasal polyps (CRSwNP), IL-37 levels in nasal secretions were reduced in patients with eosinophilic CRSwNP. Type 2 cytokines inhibited IL-37 secretion from HNECs. HNECs expressed IL-37 receptors, IL-18 receptor α, and IL-1 receptor 8. IL-37b downregulated the expression of Mex3B, a TLR3 coreceptor, in HNECs. IL-37b suppressed polyinosinic-polycytidylic acid-induced TSLP production in HNECs in vitro and in murine nasal epithelial cells in vivo. Knocking down or overexpressing Mex3B in BEAS-2B cells abolished the inhibitory effect of IL-37b. Secreted IL-37 levels negatively correlated with Mex3B and TSLP levels and eosinophil numbers in patients with eosinophilic CRSwNP. CONCLUSIONS The suppressed IL-37 secretion caused by a type 2 milieu can enhance Mex3B-mediated TLR3 activation and subsequent TSLP production in nasal epithelial cells and therefore promotes eosinophilic inflammation in patients with CRSwNP.

中文翻译：

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嗜酸性粒细胞增多性慢性鼻鼻窦炎伴鼻息肉的患者上皮细胞中的IL-37-Mex3B-Toll样受体3轴。

背景技术IL-37，一种免疫抑制性细胞因子，在炎性疾病患者中的作用尚不清楚。目的我们试图探讨IL-37在慢性鼻鼻窦炎（CRS）患者中的表达及其致病功能。方法采用定量RT-PCR，免疫组化方法研究鼻腔样本中IL-37，IL-18受体α，IL-1受体8，Mex3 RNA结合家族成员B（Mex3B）和胸腺基质淋巴细胞生成素（TSLP）的表达水平。 ，蛋白质印迹和ELISA。用各种细胞因子和Toll样受体（TLR）激动剂刺激人鼻上皮细胞（HNEC）和BEAS-2B细胞系。在某些实验中，用Mex3B小干扰RNA或过表达的慢病毒转染BEAS-2B细胞。通过使用RNA测序分析研究了HNEC中IL-37b调控的基因。在小鼠体内证实了IL-37b的功能。结果与对照组相比，在患病组织中，特别是在鼻上皮细胞，无鼻息肉的CRS患者或患有鼻息肉的慢性鼻鼻窦炎（CRSwNP）患者中，IL-37的mRNA和蛋白表达上调。嗜酸性CRSwNP患者的鼻腔分泌物水平降低。2型细胞因子抑制HNEC分泌IL-37。HNEC表达IL-37受体，IL-18受体α和IL-1受体8。IL-37b下调HNECs中TLR3受体Mex3B的表达。IL-37b抑制了HNECs体外和体内鼠鼻上皮细胞中多肌苷酸-聚胞苷酸诱导的TSLP产生。在BEAS-2B细胞中敲低或过表达Mex3B消除了IL-37b的抑制作用。嗜酸性CRSwNP患者的分泌IL-37水平与Mex3B和TSLP水平以及嗜酸性细胞数目呈负相关。结论由2型环境引起的IL-37分泌抑制可增强Mex3B介导的TLR3激活和随后鼻腔上皮细胞TSLP的产生，从而促进CRSwNP患者的嗜酸性粒细胞炎症。