Li Xiao-Jun, Huang Feng-Zhen, Wan Yan, Li Yu-Sang, Zhang Wei Kevin, Xi Yang, Tian Gui-Hua, Tang He-Bin
Department of Pharmacology, School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China.
School of Medicine, Institute of Biochemistry and Molecular Biology, Ningbo University, Ningbo, China.
Front Pharmacol. 2018 Dec 19;9:1487. doi: 10.3389/fphar.2018.01487. eCollection 2018.
How β-catenin/COX-2 contribute to inflammation-induced fibroblasts migration remains poorly understood. Therefore, in this study, lipopolysaccharide (LPS) was used as a stimulus to accelerate the migration of NIH3T3 cells, which mimicked the tissue repair process. LPS treatment increased the cell migration in concentration-and time-dependent manner. And NS398, a COX-2 inhibitor, inhibited LPS-induced NIH3T3 cells migration. DKK-1, an antagonist of the Wnt/β-catenin signaling, also inhibited that migration. However, TWS119, an inducer of β-catenin via GSK-3β, increased the cell migration. LPS or TWS119 treatment increased COX-2, β-catenin, , and expressions, and that could be attenuated by NS398 or DKK-1 addition. LPS induced the PGE production, and PGE increased the expression and nuclear translocation of β-catenin, while EP2 blocker, AH6809, alleviated those effects. TWS119 increased the luciferase activity in the COX-2 promoter. In conclusion, LPS stimulated the NIH3T3 fibroblasts migration through a positive feedback between β-catenin and COX-2, in which PGE, EP2, , and played as signal molecules.
β-连环蛋白/COX-2如何促进炎症诱导的成纤维细胞迁移仍不清楚。因此,在本研究中,使用脂多糖(LPS)作为刺激物来加速NIH3T3细胞的迁移,这模拟了组织修复过程。LPS处理以浓度和时间依赖性方式增加细胞迁移。并且,COX-2抑制剂NS398抑制LPS诱导的NIH3T3细胞迁移。Wnt/β-连环蛋白信号拮抗剂DKK-1也抑制该迁移。然而,通过GSK-3β诱导β-连环蛋白的TWS119增加了细胞迁移。LPS或TWS119处理增加了COX-2、β-连环蛋白等的表达,而添加NS398或DKK-1可减弱这种表达。LPS诱导PGE产生,PGE增加β-连环蛋白的表达和核转位,而EP2阻滞剂AH6809减轻了这些作用。TWS119增加了COX-2启动子中的荧光素酶活性。总之,LPS通过β-连环蛋白和COX-2之间的正反馈刺激NIH3T3成纤维细胞迁移,其中PGE、EP2等作为信号分子发挥作用。