背景:慢性鼻窦炎伴鼻息肉(CRSwNP)的复发率与嗜酸性粒细胞浸润呈正相关。已经报道了CRSwNP患者中白细胞介素(IL)-19和嗜酸性粒细胞趋化因子RANTES水平升高。本研究旨在阐明IL-19在嗜酸性粒细胞CRSwNP(EosCRSwNP)中介导RANTES表达和嗜酸性粒细胞浸润中的作用。
方法:鼻腔组织样本取自CRSwNP患者和对照组。IL-19及其受体的表达,ECP,并对组织中的RANTES进行了研究。原代人鼻上皮细胞(HNEC)和鼻息肉组织块培养,然后被IL-19刺激;ERK磷酸化,NF-κB通路激活,RANTES等级,使用RT-qPCR检测嗜酸性粒细胞的迁移和浸润,ELISA,西方印迹,他,免疫组织化学,免疫荧光染色,共聚焦显微镜,和transwell迁移测定。
结果:IL-19及其受体(IL-20R1/IL-20R2)的表达,嗜酸性粒细胞阳离子蛋白,与非EosCRSwNP和对照组相比,EosCRSwNP患者的鼻组织中的RANTES显着增加。IL-19与RANTES共定位在鼻组织中并且在HNECs中显著升高RANTES表达。IL-19阻断抗体和IL-20R1的siRNA敲低改善了IL-19对HNECs中RANTES分泌的影响。此外,IL-19诱导的RANTES上调与ERK和NF-κB途径的激活有关。在IL-19处理的HNECs中,NF-κB激活是由ERK途径介导的,IL-19增强鼻息肉组织块中嗜酸性粒细胞浸润。
结论:我们的研究结果表明,IL-19通过ERK/NF-κB途径促进HNECs中RANTES的表达,并参与EosCRSwNP患者的嗜酸性粒细胞浸润。
BACKGROUND: The recurrence rate of chronic rhinosinusitis with nasal polyps (CRSwNP) is positively correlated with eosinophil infiltration. Increased interleukin (IL)-19 and eosinophil chemokine
RANTES levels have been reported in patients with CRSwNP. This study aimed to clarify the role of IL-19 in mediating
RANTES expression and eosinophilic infiltration in eosinophilic CRSwNP (Eos CRSwNP).
METHODS: Nasal tissue samples were obtained from patients with CRSwNP and controls. The expression of IL-19, its receptors, ECP, and
RANTES in tissues was investigated. Primary human nasal epithelial cells (HNECs) and nasal polyp tissue blocks were cultured, then stimulated by IL-19; ERK phosphorylation, NF-κB pathway activation, RANTES level, eosinophils migration and infiltration were detected using RT-qPCR, ELISA, western blotting, HE, immunohistochemistry, immunofluorescence staining, confocal microscopy, and transwell migration assay.
RESULTS: The expression of IL-19 and its receptors (IL-20R1/IL-20R2), eosinophil cationic protein, and RANTES in nasal tissues from patients with Eos CRSwNP was significantly increased compared to that in non-Eos CRSwNP and control subjects. IL-19 co-localized with
RANTES in nasal tissues and significantly elevated
RANTES expression in HNECs. IL-19-blocking antibody and siRNA knockdown of IL-20R1 ameliorated the effect of IL-19 on RANTES secretion in HNECs. Moreover, IL-19-induced RANTES upregulation was associated with the activation of the ERK and NF-κB pathways. NF-κB activation was mediated by the ERK pathway in IL-19-treated HNECs, and IL-19 enhanced eosinophil infiltration in nasal polyp tissue blocks.
CONCLUSIONS: Our findings indicate that IL-19 promotes
RANTES expression via the ERK/NF-κB pathway in HNECs and is implicated in eosinophil infiltration in patients with Eos CRSwNP.