CXCL1 通过 CXCR2、c-Raf、MAPK 和 AP-1 通路促进骨关节炎和类风湿关节炎滑膜成纤维细胞中 IL-6 的表达。
CXCL1 contributes to IL-6 expression in osteoarthritis and rheumatoid arthritis synovial fibroblasts by CXCR2, c-Raf, MAPK, and AP-1 pathway.
机构信息
Department of Orthopedic Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, 111, Taiwan.
Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, 111, Taiwan.
出版信息
Arthritis Res Ther. 2020 Oct 21;22(1):251. doi: 10.1186/s13075-020-02331-8.
BACKGROUND
Osteoarthritis (OA) and rheumatoid arthritis (RA) are common joint disorders that are considered to be different diseases due to their unique molecular mechanisms and pathogenesis. Chemokines and their corresponding receptors have been well characterized in RA progression, but less so in OA pathogenesis.
METHODS
The human primary synovial fibroblasts (SFs) were obtained from human OA and RA tissue samples. The Western blot and qPCR were performed to analyze the expression levels of CXCL1, as well as CXCL-promoted IL-6 expression in both OASFs and RASFs. The signal cascades that mediate the CXCL1-promoted IL-6 expression were identified by using chemical inhibitors, siRNAs, and shRNAs.
RESULTS
Here, we found that both diseases feature elevated levels of CXCL1 and interleukin (IL)-6, an important proinflammatory cytokine that participates in OA and RA pathogenesis. In OASFs and RASFs, CXCL1 promoted IL-6 expression in a dose- and time-dependent manner. In OASFs and RASFs overexpressing CXCL1 or transduced with shRNA plasmid, IL-6 expression was markedly upregulated. CXCR2, c-Raf, and MAPKs were found to regulate CXCL1-induced IL-6 expression in OASFs and RASFs. Finally, CXCL1 triggered the transcriptional activities of c-Jun (which regulates the expression of proinflammatory proteins) in OASFs and RASFs.
CONCLUSIONS
Our present work suggests that the CXCL1/CXCR2 axis helps to orchestrate inflammatory responses in OA and RA SFs.
背景
骨关节炎（OA）和类风湿关节炎（RA）是常见的关节疾病，由于其独特的分子机制和发病机制，被认为是两种不同的疾病。趋化因子及其相应的受体在 RA 进展中得到了很好的描述，但在 OA 发病机制中则不然。
方法
从人 OA 和 RA 组织样本中获得人原代滑膜成纤维细胞（SFs）。通过 Western blot 和 qPCR 分析 CXCL1 的表达水平，以及 OASFs 和 RASFs 中 CXCL 促进的 IL-6 表达。通过化学抑制剂、siRNA 和 shRNA 鉴定介导 CXCL1 促进 IL-6 表达的信号级联。
结果
在这里，我们发现两种疾病都表现出 CXCL1 和白细胞介素（IL）-6 的水平升高，IL-6 是一种重要的促炎细胞因子，参与 OA 和 RA 的发病机制。在 OASFs 和 RASFs 中，CXCL1 以剂量和时间依赖的方式促进 IL-6 的表达。在过表达 CXCL1 的 OASFs 和 RASFs 或转染 shRNA 质粒中，IL-6 的表达明显上调。在 OASFs 和 RASFs 中，CXCR2、c-Raf 和 MAPKs 被发现调节 CXCL1 诱导的 IL-6 表达。最后，CXCL1 在 OASFs 和 RASFs 中触发了 c-Jun（调节促炎蛋白表达的转录因子）的转录活性。
结论
我们的研究工作表明，CXCL1/CXCR2 轴有助于协调 OA 和 RA SFs 中的炎症反应。
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