CXCL16/CXCR6 axis promotes bleomycin-induced fibrotic process in MRC-5 cells via the PI3K/AKT/FOXO3a pathway
CXCL16/CXCR6 axis promotes bleomycin-induced fibrotic process in MRC-5 cells via the PI3K/AKT/FOXO3a pathway
复制标题
CXCL16/CXCR6轴通过PI3K/AKT/FOXO3a途径促进博莱霉素诱导的MRC-5细胞纤维化过程
DOI：
10.1016/j.intimp.2019.106035
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发表时间：
2020-04-01
影响因子：
5.6
通讯作者：
Liu, Xiangyuan
中科院分区：
文献类型：
--
作者：
Ma, Zhenzhen;Yu, Ruohan;Liu, Xiangyuan
目的：间质性肺疾病（ILD）是一种进行性、不可逆的肺部疾病，治疗选择非常有限。先前的研究发现趋化因子配体CXCL 16和CXCR 6在器官纤维化中起关键作用。然而，CXCL 16和CXCR 6是否也参与ILD的发病机制，以及它们在肺纤维化中的调节作用，还没有reported.Methods：在这项研究中，我们检测CXCL 16类风湿性关节炎相关ILD（RA-ILD）患者的水平，并研究了CXCL 16/CXCR 6轴在人肺成纤维细胞（MRC-5细胞）的增殖和胶原蛋白产生中的关键作用。还评估了抗CXCL 16抗体对博莱霉素诱导的培养MRC-5细胞纤维化的影响。结果：我们的研究结果表明，RA-ILD患者血清可溶性CXCL 16明显升高，并且与肺纤维化的严重程度相关。CXCL 16通过增强MRC-5细胞的增殖、迁移和胶原蛋白产生来促进纤维化。CXCL 16可激活MRC-5细胞中PI 3 K/AK/FOX 03 a信号通路，特异性抑制剂Wortmannin和LY 294002的抑制作用，或siRNA敲低CXCR 6也可抑制CXCL 16介导的MRC-5细胞的生物学功能。结论：CXCL 16/CXCR 6轴通过PI 3 K1、AKT/FOXO 3a信号通路促进MRC-5细胞增殖和胶原合成，抑制CXCL 16/CXCR 6轴可能为肺纤维化的治疗提供新的思路。
Objective: Interstitial lung disease (ILD) is a progressive and irreversible lung disease with very limited therapeutic options. Previous studies have found that chemokine ligands CXCL16 and CXCR6 play critical roles in organ fibrosis. However, whether CXCL16 and CXCR6 are also involved in the pathogenesis of ILD, as well as their regulatory role in pulmonary fibrosis, has not been reported.Methods: In this study, we detected CXCL16 levels in patients with rheumatoid arthritis-associated ILD (RA-ILD) and examined the critical role of the CXCL16/CXCR6 axis in the proliferation and collagen production of human pulmonary fibroblasts (MRC-5 cells). The effect of anti-CXCL16 antibody on the bleomycin-induced fibrogenesis in cultured MRC-5 cells was also evaluated.Results: Our results indicated that serum soluble CXCL16 was significantly higher in RA-ILD patients and also associated with the severity of lung fibrosis. CXCL16 facilitates fibrosis by enhancing proliferation, migration, and collagen production of MRC-5 cells. Furthermore, a synergistic fibrogenic effect of CXCL16 and bleomycin has been found. CXCL16 stimulated the activation of PI3K/AK/FOX03a signaling pathway in MRC-5 cells, and the inhibition by specific inhibitors Wortmannin and LY294002, or knockdown of CXCR6 by siRNA also suppressed the biological functions of MRC-5 cells mediated by CXCL16. Similarly, down-regulation of CXCR6 also partly blocked BLM-induced fibrogenesis in MRC-5 cells.Conclusions: CXCL16/CXCR6 axis promotes proliferation and collagen production of MRC-5 cells by the PI3K1 AKT/FOXO3a signaling pathway, and inhibition of the CXCL16/CXCR6 axis may provide a new therapeutic strategy targeting pulmonary fibrosis.