Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: Important implications in asthma
Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: Important implications in asthma
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DOI：
10.1016/j.jaci.2008.04.016
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发表时间：
2008-06-01
影响因子：
14.2
通讯作者：
Wu, Reen
中科院分区：
文献类型：
--
作者：
Huang, Fei;Wachi, Shinichiro;Wu, Reen
背景：IL-17A和IL-19在银屑病、哮喘等慢性炎症性疾病中高表达。IL-19在变应性疾病中增强T(H)2细胞因子分泌中发挥重要作用，但其在哮喘患者中的细胞来源尚不清楚。目的：我们的目的是确定上皮是否是气道黏膜IL-19的主要来源，并阐明基因表达调控的机制。方法：采用免疫荧光染色法检测各种气道疾病气管组织切片中IL-19蛋白的表达。以分化良好的原代人支气管上皮细胞培养物和相应的细胞系作为体外模型研究基因调控。结果：哮喘患者气道上皮IL-19表达明显高于其他疾病患者。通过细胞因子面板，我们发现除了之前发现的T(H)17细胞因子IL-17A外，两种TH2细胞因子IL-4和IL-13也能上调IL-19在培养中的表达。此外，IL-17A和IL-4/11L-13共处理可协同上调IL-19的表达。使用siRNA和化学抑制剂方法，我们证明了核因子kappa B和转录信号转换器和激活因子（STAT）对IL-19的转录调节6。将IL-13添加到IL-17A刺激中会触发从依赖核因子κ b的转录调控转变为基于STAT6的转录调控。通过染色质免疫沉淀试验，我们证实了在IL-19启动子区域存在stat6结合元件。结论：我们认为IL-17A-和il -13诱导的IL-19刺激气道上皮的协同作用是通过stat6依赖途径发生的。
Background: IL-17A and IL-19 are highly expressed in chronic inflammatory diseases, such as psoriasis and asthma. IL-19 plays a significant role in the enhancement of T(H)2 cytokine secretion in allergic diseases, but its cellular source in asthmatic patients remains unknown.Objective: Our aims were to determine whether the epithelium is a major source of airway mucosal IL-19 and to elucidate the mechanism of gene expression regulation.Methods: Immunofluorescent staining was used to determine IL-19 protein expression in tracheal tissue sections of various airway diseases. Well-differentiated primary human bronchial epithelial cultures and a corresponding cell line were used as in vitro models to study gene regulation.Results: We found significantly higher IL-19 expression in airway epithelia of asthmatic patients than in epithelia of patients with other diseases. Using a cytokine panel, we demonstrated the upregulation of IL-19 expression in cultures by two TH2 cytokines, IL-4 and IL-13, in addition to the previously found T(H)17 cytokine IL-17A. Moreover, cotreatment of IL-17A and IL-4/11L-13 synergistically upregulated IL-19 expression. Using siRNA and chemical inhibitor approaches, we demonstrated a transcriptional regulation of IL-19 by nuclear factor kappa B and signal transducer and activator of transcription (STAT) 6. The addition of IL-13 to IL-17A stimulation triggers a shift from nuclear factor kappa B-dependent transcriptional regulation to one that is STAT6 based. Using chromatin immunoprecipitation assays, we demonstrated the presence of STAT6-binding elements in the IL-19 promoter region.Conclusion: We propose that an IL-17A- and IL-13-induced synergism in IL-19 stimulation in airway epithelia occurs through a STAT6-dependent pathway.