Department of Rheumatology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China.
Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China.
J Cell Physiol. 2019 Nov;234(11):20139-20148. doi: 10.1002/jcp.28615. Epub 2019 Apr 13.
Fibroblast-like synoviocytes (FLS), synovial tissue-specific cells, are key effector cells during the pathogenesis of rheumatoid arthritis (RA). Our previous study has shown that tripartite motif-containing protein 3 (TRIM3) overexpression inhibits the proliferation and cytokine secretion of RA FLS. Experiments with gene knockout mice have suggested the important roles of forkhead box o3a (Foxo3a) in RA pathogenesis. The present study aimed to investigate the correlation between Foxo3a and TRIM3 during RA pathogenesis. The expression of Foxo3a and TRIM3 was reduced in RA synovial tissues in comparison to healthy controls, and Foxo3a messenger RNA (mRNA) expression in RA synovial tissues correlated positively with TRIM3 mRNA expression. We found that stimulation with lipopolysaccharide (LPS) caused the downregulation of Foxo3a and TRIM3 in FLS. Foxo3a or TRIM3 overexpression significantly attenuated the promoting effects of LPS on cell proliferation and the release of tumor necrosis factor-α, interleukin-6 (IL-6), and IL-1β. In addition, Foxo3a suppressed the inhibitory effects of LPS on the mRNA and protein levels of TRIM3, as well as the activity of TRIM3 promoter. Foxo3a or TRIM3 overexpression attenuated collagen-induced arthritis in rats. Furthermore, knockdown of TRIM3 significantly suppressed the effects of Foxo3a overexpression on LPS-activated FLS. In summary, our findings suggested that Foxo3a exerted inhibitory effects on LPS-induced proliferation and inflammation through increasing TRIM3 transcription. The decreased expression of Foxo3a may contribute to the RA pathogenesis.
成纤维样滑膜细胞（FLS）是滑膜组织特异性细胞，是类风湿关节炎（RA）发病机制中的关键效应细胞。我们之前的研究表明，三结构域蛋白 3（TRIM3）过表达抑制 RA FLS 的增殖和细胞因子分泌。基因敲除小鼠实验表明叉头框蛋白 O3a（Foxo3a）在 RA 发病机制中起重要作用。本研究旨在探讨 RA 发病过程中 Foxo3a 与 TRIM3 之间的相关性。与健康对照组相比，RA 滑膜组织中 Foxo3a 和 TRIM3 的表达降低，且 RA 滑膜组织中 Foxo3a mRNA 表达与 TRIM3 mRNA 表达呈正相关。我们发现，脂多糖（LPS）刺激导致 FLS 中 Foxo3a 和 TRIM3 的下调。Foxo3a 或 TRIM3 的过表达显著减弱了 LPS 对细胞增殖和肿瘤坏死因子-α、白细胞介素-6（IL-6）和白细胞介素-1β释放的促进作用。此外，Foxo3a 抑制了 LPS 对 TRIM3 mRNA 和蛋白水平以及 TRIM3 启动子活性的抑制作用。Foxo3a 或 TRIM3 的过表达可减轻大鼠胶原诱导性关节炎。此外，TRIM3 的敲低显著抑制了 Foxo3a 过表达对 LPS 激活的 FLS 的作用。综上所述，我们的研究结果表明，Foxo3a 通过增加 TRIM3 的转录来抑制 LPS 诱导的增殖和炎症反应。Foxo3a 表达降低可能导致 RA 发病。
