MicroRNA-133α regulates neurotensin-associated colonic inflammation in colonic epithelial cells and experimental colitis

Abstract

Ulcerative colitis (UC) and Crohn’s Disease (CD) are the two most common forms of Inflammatory Bowel Diseases (IBD) marked by chronic and persistent inflammation. Neurotensin (NT), together with its receptor, NT receptor 1 (NTR1), are important mediators in intestinal inflammation and their expression is upregulated in the intestine of experimental colitis models and UC colonic biopsies. MicroRNAs (miRNAs) are short, non-coding RNA molecules which act as transcription repressors. We have previously shown that NT exposure upregulates miR-133α expression in human colonocytes NCM460 cells overexpressing NTR1 (NCM460-NTR1). Recently, miR-133α was further examined forits role in NT-associated proinflammatory signaling cascades and acute colitis in vivo. Our study shows that NT-induced miR-133α upregulation modulates NF-κB phosphorylation and promotes proinflammatory cytokine production. In addition, intracolonicinjection of antisense-miR-133α before colitis induction improves histological scores and proinflammatory cytokine transcription. More importantly, dysregulation of miR-133α levels and aftiphilin (AFTPH), a newly-identified miR-133α downstream target, is found only in UC patients, but not in patients with CD. Taken together, we identified NTR1/miR-133α/aftiphilin as a novel regulatory axis involved in NT-associated colonic inflammation in human colonocytes, acute colitis mouse model and in colonic biopsies from UC patients. Our results also provide evidence that colonic levels of NTR1, miR-133α and aftiphilin may also serve as potential biomarkers in UC.

Inhibition of Aberrant MicroRNA-133a Expression in Endothelial Cells by Statin Prevents Endothelial Dysfunction by Targeting GTP Cyclohydrolase 1 in Vivo

“…21,29–32 In epithelial cells, miR-133a is upregulated by neurotensin to mediate colonic inflammation. 33 In this study, we further demonstrated that GCH1 mRNA is a target of miR-133a in endothelial cells. Although GCH1 gene expression is regulated posttranslationally, such as by the ubiquitin-proteasome pathway and phosphorylation, 25,34,35 this study is the first to ascertain that GCH1 mRNA stability is determined by miR-133a.…”

Salidroside downregulates microRNA‑133a and inhibits endothelial cell apoptosis induced by oxidized low‑density lipoprotein

“…Previous studies have found that miR-133a is a muscle-specific miRNA that plays an essential role in the normal development and function of the skeletal muscle and myocardium ( 38 , 39 ). In addition, epithelial cell miR-133a expression has been reported to be upregulated by neurotensin, which mediates colitis ( 40 ). The present study found that miR-133a can regulate the transcript levels of the anti-apoptotic protein Bcl-xL, thereby highlighting its role in the process of endothelial cell apoptosis.…”

The emerging role of lncRNAs in inflammatory bowel disease

“…A 13 amino acid length neuropeptide, neurotensin (NT), together with its high affinity G protein-coupled receptor 1 (NTR1), are believed to promote the development of UC and are expressed in the colon where they are upregulated in animal colitis models and UC patients 51 – 54 . NT/NTR1 signaling is involved in various colonic responses, including proinflammatory responses, and regulates several miRNAs associated with intestinal inflammation 55 , 56 . Law et al 57 investigated the effect of NT stimulation on the lncRNA profile of human colonic epithelial cells (NCM460) with NTR1 overexpression.…”