MiR-125-5p/IL-6R axis regulates macrophage inflammatory response and intestinal epithelial cell apoptosis in ulcerative colitis through JAK1/STAT3 and NF-κB pathway

• Published in: Cell cycle (Georgetown, Tex.) Tex.), 2021-12, Vol.20 (23), p.2547-2564
• Main Authors: Yao, Danhua, Zhou, Zhiyuan, Wang, Pengfei, Zheng, Lei, Huang, Yuhua, Duan, Yantao, Liu, Bin, Li, Yousheng
• Format: Article
• Language: English
• Subjects: Animals; apoptosis; Apoptosis - genetics; Colitis, Ulcerative - genetics; Colitis, Ulcerative - metabolism; Colitis, Ulcerative - pathology; Disease Models, Animal; Epithelial Cells - metabolism; Humans; inflammatory; interleukin 6 receptor; Janus Kinase 1 - genetics; Janus Kinase 1 - metabolism; Macrophages - metabolism; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; MiR-125-5p; NF-kappa B - metabolism; Receptors, Interleukin-6 - genetics; Receptors, Interleukin-6 - metabolism; Research Paper; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Ulcerative colitis
• ISSN: 1538-4101; 1551-4005
• DOI: 10.1080/15384101.2021.1995128

This study explored the effects of miR-125-5p and interleukin-6 receptor (IL-6 R) on ulcerative colitis (UC) cell models and mouse models. The sera derived from UC patients and healthy subjects were collected for expression analysis. UC in vitro models and in vivo model were constructed and used. Expressions of miR-125-5p, IL-6 R, AK1/STAT3 and NF-κB pathways, and inflammatory factors, histopathology and apoptosis were determined by conducting a series of molecular experiments. The relationship between miR-125-5p and IL-6 R was analyzed by TargetScan7.2 and verified by dual-luciferase assay. The disease activity index (DAI) score, weight change, and colon length of the mice were recorded and analyzed. Decreased expression of miR-125-5p in the sera of UC patients was related to the increased expression of its target gene IL-6 R. In vitro, up-regulation of miR-125-5p decreased IL-6 R expression, contents of inflammatory factors in THP-1 cells and cell apoptosis of NCM460, and inhibited the activation of JAK1/STAT3 and NF-κB pathway. However, down-regulation of miR-125-5p produced the opposite effects to its up-regulation. IL-6 R overexpression partially reversed the effects of miR-125-5p up-regulation on UC cell models. In vivo, miR-125-5p overexpression significantly improved the severity of colitis, including DAI score, colon length, tissue damage, apoptosis, and inflammatory response, in the mice in the UC group. In addition, miR-125-5p up-regulation significantly reduced the expression of IL-6 R in the UC mice, and reduced the expression levels of JAK1, STAT3 and p65 phosphorylation. MiR-125-5p targeting IL-6 R regulates macrophage inflammatory response and intestinal epithelial cell apoptosis in ulcerative colitis through JAK1/STAT3 and NF-κB pathway.