Purpose. Asthma is one of the most common obstructive pulmonary diseases worldwide. Epigenetic alterations, including DNA methylation and histone modifications, have been reported to contribute to asthma pathogenesis. Since the inflammation mediator and remodeling trigger, IL-13, is known to play a central role in the pathophysiology of asthma, this study was aimed to identify novel IL-13-regulated epigenetic modifiers in asthma that may contribute to subepithelial fibrosis. Methods. Publicly available transcriptomic datasets from Gene Expression Omnibus (GEO) were used to identify differentially expressed genes on an epigenetic level upon IL-13 exposure in lung fibroblasts. Bronchial fibroblasts isolated from healthy and asthmatic individuals were assessed for the gene and protein expression levels of the identified gene at baseline and upon IL-13 treatment using qRT-PCR and western blotting, respectively. Its subcellular localization and tissue distribution were examined in bronchial fibroblasts as well as bronchial biopsies by immunofluorescence and immunohistochemical analysis, respectively. Results. Bioinformatic analysis revealed the differential expression of the histone demethylase JMJD2B/KDM4B, a well-known epigenetic modulator that leads to the demethylation of different lysine residues on histones, in IL-13-treated lung fibroblasts. The baseline expression levels of JMJD2B were higher in asthmatic fibroblasts and in bronchial biopsies in comparison to healthy ones. There was also an increase in JMJD2B activity as evidenced by the demethylation of its downstream target, H3K36me3. Furthermore, IL-13 stimulation induced JMJD2B expression and further demethylation of H3K36me3 in asthmatic fibroblasts. This was accompanied by increased translocation of JMJD2B into the nucleus. Conclusion. This study highlights the novel pathological involvement of the histone demethylase JMJD2B/KDM4B in asthmatic airway fibroblasts that are regulated by IL-13. Clinical implications. Given that there is no single therapeutic medicine to effectively treat the various subtypes of asthma, this study provides promising insights into JMJD2B as a new therapeutic target that could potentially improve the treatment and management of asthma.

中文翻译：

---

IL-13 增强哮喘患者气道成纤维细胞中组蛋白去甲基化酶 JMJD2B/KDM4B 的表达水平、活性和核转位

目的。哮喘是世界范围内最常见的阻塞性肺疾病之一。据报道，包括 DNA 甲基化和组蛋白修饰在内的表观遗传改变有助于哮喘发病机制。由于已知炎症介质和重塑触发因素 IL-13 在哮喘的病理生理学中发挥核心作用，因此本研究旨在确定哮喘中可能导致上皮下纤维化的新型 IL-13 调节的表观遗传修饰物。方法. 来自 Gene Expression Omnibus (GEO) 的公开可用的转录组数据集被用于识别肺成纤维细胞中 IL-13 暴露后表观遗传水平上的差异表达基因。分别使用 qRT-PCR 和蛋白质印迹在基线和 IL-13 治疗后评估从健康和哮喘个体分离的支气管成纤维细胞的基因和蛋白质表达水平。分别通过免疫荧光和免疫组织化学分析在支气管成纤维细胞和支气管活检中检查其亚细胞定位和组织分布。结果. 生物信息学分析揭示了在 IL-13 处理的肺成纤维细胞中组蛋白去甲基化酶 JMJD2B/KDM4B 的差异表达，这是一种众所周知的表观遗传调节剂，可导致组蛋白上不同赖氨酸残基的去甲基化。与健康人相比，哮喘成纤维细胞和支气管活检中 JMJD2B 的基线表达水平更高。JMJD2B 的活性也有所增加，其下游靶标 H3K36me3 的去甲基化证明了这一点。此外，IL-13 刺激诱导哮喘成纤维细胞中 JMJD2B 表达和 H3K36me3 进一步去甲基化。这伴随着增加的 JMJD2B 易位到细胞核中。结论. 该研究强调了组蛋白去甲基化酶 JMJD2B/KDM4B 在受 IL-13 调节的哮喘气道成纤维细胞中的新病理参与。临床意义。鉴于没有单一的治疗药物可以有效治疗各种哮喘亚型，这项研究为 JMJD2B 作为可能改善哮喘治疗和管理的新治疗靶点提供了有希望的见解。