Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Division for Health Service Promotion, The University of Tokyo, Tokyo, Japan; Division of Pulmonary, Critical Care and Sleep Medicine and Hastings Center for Pulmonary Research, Department of Medicine, and Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Allergol Int. 2019 Jan;68(1):101-109. doi: 10.1016/j.alit.2018.08.005. Epub 2018 Sep 6.
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.
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.
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.
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.
支气管哮喘是一种慢性气道疾病，其特征是嗜酸性粒细胞性气道炎症。IL-13 激活的肺成纤维细胞可作为趋化因子（如 eotaxin）的重要来源，从而导致持续的嗜酸性粒细胞炎症。含Src 同源结构域 2 的蛋白（CISH）属于细胞因子信号转导抑制因子（SOCS）家族，作为细胞因子诱导的负调节剂。本研究旨在阐明 CISH 在人肺成纤维细胞嗜酸性粒细胞趋化性趋化因子产生中的作用。
用 IL-13 刺激正常人肺成纤维细胞，并通过 cDNA 微阵列评估其全基因表达谱。通过定量 RT-PCR、ELISA 或 Western blot 评估 IL-13 信号转导的表达变化及其下游途径。通过小干扰 RNA 和载体过表达分别进行 CISH 的功能丧失和功能获得分析。
Ingenuity 通路分析表明，IL-13 诱导趋化因子信号转导，包括 eotaxin 家族，同时显著抑制 IFN-α/β 信号转导。在 8 种 SOCS 家族成员中，CISH 是 IL-13 通过信号转导和转录激活因子 6（STAT6）磷酸化最强诱导的。功能丧失和功能获得研究表明，CISH 负调控 CCL26 的表达。
这些发现表明，CISH 通过调节 IL-13 诱导的 CCL26 产生，在与支气管哮喘相关的嗜酸性粒细胞炎症中发挥关键作用。增强 CISH 功能可能是治疗重症哮喘嗜酸性粒细胞炎症的一种新方法。
