Department of Respiratory Medicine, The Fourth Affiliated Hospital of China Medical University/China Medical University, Seven South Road, Shenyang, 110005, Liaoning, China.
Emergency Department, The Fourth Affiliated Hospital of China Medical University/China Medical University, Seven South Road, Shenyang, 110005, Liaoning, China.
Respir Res. 2021 Oct 28;22(1):280. doi: 10.1186/s12931-021-01858-x.
IL-35 subunit EBI3 is up-regulated in pulmonary fibrosis tissues. In this study, we investigated the pathological role of EBI3 in pulmonary fibrosis and dissected the underlying molecular mechanism.
Bleomycin-induced pulmonary fibrosis mouse model was established, and samples were performed gene expression analyses through RNAseq, qRT-PCR and Western blot. Wild type and EBI3 knockout mice were exposed to bleomycin to investigate the pathological role of IL-35, via lung function and gene expression analyses. Primary lung epithelial cells were used to dissect the regulatory mechanism of EBI3 on STAT1/STAT4 and STAT3.
IL-35 was elevated in both human and mouse with pulmonary fibrosis. EBI3 knockdown aggravated the symptoms of pulmonary fibrosis in mice. EBI3 deficiency enhanced the expressions of fibrotic and extracellular matrix-associated genes. Mechanistically, IL-35 activated STAT1 and STAT4, which in turn suppressed DNA enrichment of STAT3 and inhibited the fibrosis process.
IL-35 might be one of the potential therapeutic targets for bleomycin-induced pulmonary fibrosis.
IL-35 亚基 EBI3 在肺纤维化组织中上调。在这项研究中，我们研究了 EBI3 在肺纤维化中的病理作用，并剖析了潜在的分子机制。
建立博来霉素诱导的肺纤维化小鼠模型，并通过 RNAseq、qRT-PCR 和 Western blot 进行基因表达分析。通过肺功能和基因表达分析，使野生型和 EBI3 敲除小鼠暴露于博来霉素中，以研究 IL-35 的病理作用。使用原代肺上皮细胞来剖析 EBI3 对 STAT1/STAT4 和 STAT3 的调控机制。
肺纤维化患者和小鼠的 IL-35 水平均升高。EBI3 敲低加重了小鼠的肺纤维化症状。EBI3 缺乏增强了纤维化和细胞外基质相关基因的表达。机制上，IL-35 激活了 STAT1 和 STAT4，进而抑制了 STAT3 的 DNA 富集并抑制了纤维化过程。
IL-35 可能是博来霉素诱导的肺纤维化的潜在治疗靶点之一。
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