miR-642a-5p increases glucocorticoid sensitivity by suppressing the TLR4 signalling pathway in THP-1 cells

Juan Luo; Yijie Wang; Xiangqian Dong; Wen Wang; Yanju Mu; Yang Sun; Fengrui Zhang; Yinglei Miao

doi:10.1016/j.bbrep.2022.101356

miR-642a-5p increases glucocorticoid sensitivity by suppressing the TLR4 signalling pathway in THP-1 cells

Biochem Biophys Rep. 2022 Sep 27:32:101356. doi: 10.1016/j.bbrep.2022.101356. eCollection 2022 Dec.

Authors

Juan Luo¹, Yijie Wang², Xiangqian Dong¹, Wen Wang¹, Yanju Mu¹, Yang Sun¹, Fengrui Zhang¹, Yinglei Miao¹

Affiliations

¹ Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China.
² Department of Intensive Care Unit, The First Affiliated Hospital of Kunming Medical University, Kunming, China.

Abstract

The incidence rate of ulcerative colitis (UC) is increasing annually, and glucocorticoid (GC) resistance (GCR) is a common cause of UC-induced remission failure. Our previous studies have shown that the expression of miR-642a-5p is downregulated in UC with GCR, suggesting that miR-642a-5p may be related to the GC response. Therefore, we investigated the mechanism by which miR-642a-5p regulates the GC response in THP-1 cells. We found that after treatment with miR-642a-5p mimics and DEX, the expression levels of glucocorticoid receptor (GR) in the nucleus and NF-κB p65 and p50 in the cytoplasm were increased (P < 0.05). miR-642a-5p mimics transfected into THP-1 cells could synergize with dexamethasone (DEX) to reduce lipopolysaccharide (LPS)-induced inflammatory factor levels such as TNF-α, IL-1β, IL-6 and IL-12 (P < 0.05). Bioinformatics analysis and luciferase reporter assays confirmed that TLR4 is a target gene of miR-642a-5p. miR-642a-5p mimic pretreatment enhanced the inhibitory effect of DEX on TLR4 induced by LPS and inhibited the expression of TLR4 on the cell surface (P < 0.05). Additionally, miR-642a-5p further prevented the nuclear import of NF-κB P65 and inhibited the phosphorylation of ERK, p38 and JNK. These results suggest that miR-642a-5p can inhibit the inflammation by suppressing the TLR4 signalling pathway in THP-1 cells. It also highlights the TLR4 signalling pathway as a potential therapeutic target in anti-inflammation.

Keywords: GCR, Glucocorticoid resistance; Glucocorticoid resistance; Glucocorticoid sensitivity; TLR4, Toll-like receptor 4; Toll-like receptor 4; Ulcerative colitis; miR-642a-5p.