Interleukin-18 promotes fibroblast senescence in pulmonary fibrosis through down-regulating Klotho expression.
Interleukin-18 promotes fibroblast senescence in pulmonary fibrosis through down-regulating Klotho expression.
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DOI：
10.1016/j.biopha.2019.108756
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发表时间：
2019-05
期刊：
影响因子：
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通讯作者：
Li-Ming Zhang;Jun Zhang;Ying Zhang;Chang Fei;Lin Wang;Zong-Wei Yi;Zai-Qi Zhang
中科院分区：
文献类型：
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作者：
Li-Ming Zhang;Jun Zhang;Ying Zhang;Chang Fei;Lin Wang;Zong-Wei Yi;Zai-Qi Zhang
特发性肺纤维化（IPF）是一种病因不明的致死性疾病，主要发生在老年人中。与衰老相关的机制（如成纤维细胞衰老）与IPF的病理学密切相关。我们先前已经证明了IL-18结合蛋白（IL-18 BP）通过促进上皮细胞向间质细胞转化对博莱霉素（BLM）诱导的肺纤维化（PF）的保护作用。然而，IL-18在PF成纤维细胞衰老中的作用仍然未知。本研究旨在探讨IL-18对肺成纤维细胞衰老的影响。结果发现，BLM攻击小鼠肺成纤维细胞SA-β-gal阳性细胞增多，G1期细胞比例增加，p21和p53表达增加，而IL-18 BP处理小鼠肺成纤维细胞衰老倾向降低。我们进一步证明IL-18足以触发原代肺成纤维细胞的衰老。用IL-18处理的成纤维细胞的衰老相关分泌表型（SASP）强烈刺激肺成纤维细胞中的纤维化表型。此外，Klotho，一种抗衰老蛋白，在IL-18处理后在原代肺成纤维细胞中的表达下调。过表达Klotho可逆转IL-18诱导的肺成纤维细胞衰老和SASP。综上所述，我们首次报道了IL-18通过阻断Klotho通路促进PF肺成纤维细胞衰老和SASP。IL-18 BP中和IL-18后，可部分抑制PF肺成纤维细胞的衰老，从而发挥抗纤维化作用，IL-18可能成为PF治疗的靶点。
Idiopathic pulmonary fibrosis (IPF) is a lethal disease of unknown aetiology that largely presents in the elderly. The mechanisms related to aging such as fibroblast senescence have been strongly implicated in pathology of IPF. We have previously demonstrated the protective effects of IL-18 binding protein (IL-18BP) against bleomycin (BLM)-induced pulmonary fibrosis (PF)viainhibition of epithelial-to-mesenchymal transition. However, the role of IL-18 in fibroblast senescence in PF is still unknown. The aim of this study was to investigate the effects of IL-18 on fibroblast senescence in the development of PF. We found that SA-β-gal positive cells, the proportion of cells in G1 phase, and expressions of p21 and p53 were increased in primary lung fibroblasts isolated from BLM-challenged mice, while the fibroblasts from IL-18BP-treated mice showed decreased senescence propensity. We further demonstrated that IL-18 was sufficient to trigger senescence of primary lung fibroblasts. The senescence-associated secretory phenotype (SASP) of fibroblasts treated with IL-18 robustly stimulated a fibrotic phenotype in pulmonary fibroblasts. Moreover, the expression of Klotho, an anti-senescence protein, was down-regulated after IL-18 treatment in primary lung fibroblasts. Overexpression of Klotho reversed the senescence and SASP induced by IL-18 in lung fibroblasts. In summary, we reported for the first time that IL-18 promoted the lung fibroblast senescence and SASP in PF through blocking Klotho pathway. Neutralize IL-18 by IL-18BP exhibited antifibrotic effects partly by suppressing lung fibroblast senescence in PF. It contributes to the growing evidence that IL-18 could be a therapeutic target for PF.