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

Inflammatory Bowel Disease (IBD), which includes ulcerative colitis (UC) and Crohn’s Disease (CD), are gastrointestinal disorders characterized by chronic and persistent inflammation. Neurotensin (NT), together with its high-affinity receptor NT receptor 1 (NTR1) are important mediators in intestinal inflammation and their expression is increased in the intestine of experimental colitis models and UC colonic biopsies. MicroRNAs (miRNAs) are short, single-stranded, non-coding RNA molecules which act as negative transcription regulators. We have previously shown that NT exposure upregulates miR-133α expression in human colonic epithelial NCM460 cells overexpressing NTR1 (NCM460-NTR1). Recently, we have further investigated the role of miR-133α in regulation of NT-associated proinflammatory signaling cascades and acute colitis in vivo. Our study shows that NT-induced miR-133α upregulation lead to NF-κB activation and increased production of proinflammatory cytokines. In addition, intracolonic administration of antisense-miR-133α prior to colitis induction improves histological scores and proinflammatory cytokine production. More importantly, dysregulation of miR-133α levels and aftiphilin (AFTPH), a novel miR-133α downstream target, are found only in patients with UC patients, but not with CD. Taken together, we have identified NTR1/miR-133α/aftiphilin as a novel regulatory axis involved in NT-associated colonic inflammation in vitro and in vivo. Our results also provide evidence that colonic levels of NTR1, miR-133a and aftiphilin may also serve as potential biomarkers in UC

A long noncoding RNA signature for ulcerative colitis identifies IFNG-AS1 as an enhancer of inflammation

High-throughput technologies revealed new categories of genes, including the long noncoding RNAs (lncRNAs), involved in the pathogenesis of human disease; however, the role of lncRNAs in the ulcerative colitis (UC) has not been evaluated. Gene expression profiling was used to develop lncRNA signatures in UC samples. Jurkat T cells were activated by PMA/ionomycin subsequently interferon- (IFNG) and tumor necrosis factor (TNF)- protein levels were assessed by ELISA. Anti-sense molecules were designed to block IFNG-AS1 expression. A unique set of lncRNAs was differentially expressed between UC and control samples. Of these, IFNG-AS1 was among the highest statistically significant lncRNAs (fold change: 5.27, P value: 7.07E-06). Bioinformatic analysis showed that IFNG-AS1 was associated with the IBD susceptibility loci SNP rs7134599 and its genomic location is adjacent to the inflammatory cytokine IFNG. In mouse models of colitis, active colitis samples had increased colonic expression of this lncRNA. Utilizing the Jurkat T cell model, we found IFNG-AS1 to positively regulate IFNG expression. Novel lncRNA signatures differentiate UC patients with active disease, patients in remission, and control subjects. A subset of these lncRNAs was found to be associated with the clinically validated IBD susceptibility loci. IFNG-AS1 was one of these differentially expressed lncRNAs in UC patients and found to regulate the key inflammatory cytokine, IFNG, in CD4 T cells. Taking these findings together, our study revealed novel lncRNA signatures deregulated in UC and identified IFNG-AS1 as a novel regulator of IFNG inflammatory responses, suggesting the potential importance of noncoding RNA mechanisms on regulation of inflammatory bowel disease-related inflammatory responses

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

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

microRNA-133? regulates neurotensin-associated colonic inflammation in colonic epithelial cells and experimental colitis: DOI: 10.14800/rd.472

Inflammatory Bowel Disease (IBD), which includes ulcerative colitis (UC) and Crohn’s Disease (CD), are gastrointestinal disorders characterized by chronic and persistent inflammation. Neurotensin (NT), together with its high-affinity receptor NT receptor 1 (NTR1) are important mediators in intestinal inflammation and their expression is increased in the intestine of experimental colitis models and UC colonic biopsies. MicroRNAs (miRNAs) are short, single-stranded, non-coding RNA molecules which act as negative transcription regulators. We have previously shown that NT exposure upregulates miR-133? expression in human colonic epithelial NCM460 cells overexpressing NTR1 (NCM460-NTR1). Recently, we have further investigated the role of miR-133? in regulation of NT-associated proinflammatory signaling cascades and acute colitis in vivo. Our study shows that NT-induced miR-133? upregulation lead to NF-?B activation and increased production of proinflammatory cytokines. In addition, intracolonic administration of antisense-miR-133? prior to colitis induction improves histological scores and proinflammatory cytokine production. More importantly, dysregulation of miR-133? levels and aftiphilin (AFTPH), a novel miR-133? downstream target, are found only in patients with UC patients, but not with CD. Taken together, we have identified NTR1/miR-133?/aftiphilin as a novel regulatory axis involved in NT-associated colonic inflammation in vitro and in vivo. Our results also provide evidence that colonic levels of NTR1, miR-133a and aftiphilin may also serve as potential biomarkers in UC

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

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