CISH is a negative regulator of IL-13-induced CCL26 production in lung fibroblasts
CISH is a negative regulator of IL-13-induced CCL26 production in lung fibroblasts
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CISH 是肺成纤维细胞中 IL-13 诱导的 CCL26 产生的负调节因子
DOI：
10.1016/j.alit.2018.08.005
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发表时间：
2019
影响因子：
6.8
通讯作者：
Yamauchi Yasuhiro
中科院分区：
文献类型：
--
作者：
Takeshima Hideyuki;Horie Masafumi;Mikami Yu;Makita Kosuke;Miyashita Naoya;Matsuzaki Hirotaka;Noguchi Satoshi;Urushiyama Hirokazu;Hiraishi Yoshihisa;Mitani Akihisa;Borok Zea;Nagase Takahide;Yamauchi Yasuhiro
背景：支气管哮喘是一种以嗜酸性粒细胞性气道炎症为特征的慢性气道疾病。由IL-13激活的肺成纤维细胞作为趋化因子（如嗜酸性粒细胞趋化因子）的重要来源，导致持续的嗜酸性粒细胞炎症。含Src同源蛋白2（CISH）属于细胞因子信号转导抑制因子（SOCS）家族，是细胞因子诱导的负调节因子。本研究的目的是阐明CISH在人肺成纤维细胞产生嗜酸性粒细胞趋化因子中的作用。方法：用IL-13刺激正常人肺成纤维细胞，用基因芯片检测CISH基因表达谱。通过定量RT-PCR、ELISA或蛋白质印迹法评估IL-13信号传导的表达变化和下游。结果：IL-13可诱导包括eotaxin家族在内的趋化因子信号通路，同时显著抑制IFN-α/β信号通路。在8个SOCS家族成员中，IL-13通过信号转导和转录激活因子6（STAT 6）的磷酸化诱导CISH最强。结论：CISH通过调节IL-13诱导的CCL 26的表达，在哮喘嗜酸性粒细胞炎症中发挥重要作用。增强CISH功能可能是治疗重度哮喘患者嗜酸性粒细胞炎症的一种新方法。
Background: Bronchial asthma is a chronic airway disease characterized by eosinophilic airway inflammation. Lung fibroblasts activated by IL-13 serve as important sources of chemokines, such as eotaxins, contributing to persistent eosinophilic inflammation. Src-homology 2-containing protein (CISH), belonging to the suppressor of cytokine signaling (SOCS) family, acts as a negative regulator of cytokine induction. The aim of this study was to elucidate the role of CISH in the production of eosinophil chemotactic chemokines in human lung fibroblasts.Methods: Normal human lung fibroblasts were stimulated by IL-13, and global gene expression profile was assessed by cDNA microarray. Expression changes and downstream of IL-13 signaling were evaluated by quantitative RT-PCR, ELISA or western blotting. Loss-and gain-of-function analyses of CISH were performed by small interfering RNA and vector overexpression, respectively.Results: Ingenuity pathway analysis revealed that IL-13 induced chemokine signaling, including the eotaxin family, while significantly suppressing IFN-α/β signaling. Among eight SOCS family members, CISH was most strongly induced by IL-13 via phosphorylation of signal transducer and activator of transcription 6 (STAT6). Loss-and gain-of-function studies demonstrated that CISH negatively regulated the expression of CCL26.Conclusions: These findings suggest that CISH plays a key role in the eosinophilic inflammation associated with bronchial asthma by regulating IL-13-induced CCL26 production. Augmentation of CISH function could be a novel approach for treating eosinophilic inflammation in severe asthma.