title: Neurotensin--regulated miR-133α is involved in proinflammatory signalling in human colonic epithelial cells and in experimental colitis.
abstract: OBJECTIVE
  Neurotensin (NT) mediates colonic inflammation through its receptor neurotensin receptor 1 (NTR1). NT stimulates miR-133α expression in colonic epithelial cells. We investigated the role of miR-133α in NT-associated colonic inflammation in vitro and in vivo.
  
  
  METHODS
  miR-133α and aftiphilin (AFTPH) levels were measured by quantitative PCR. Antisense (as)-miR-133α was administrated intracolonicaly prior to induction of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis and dextran sodium sulfate (DSS)-induced colitis. The effect of AFTPH was examined by gene silencing in vitro.
  
  
  RESULTS
  NT increased miR-133α levels in NCM-460 overexpressing NTR1 (NCM460-NTR1) and HCT-116 cells. NT-induced p38, ERK1/2, c-Jun, and NF-κB activation, as well as IL-6, IL-8 and IL-1β messenger RNA (mRNA) expression in NCM-460-NTR1 cells were reduced in miR-133α-silenced cells, while overexpression of miR-133α reversed these effects. MiR-133α levels were increased in TNBS (2 day) and DSS (5 day) colitis, while NTR1 deficient DSS-exposed mice had reduced miR-133α levels, compared to wild-type colitic mice. Intracolonic as-miR-133α attenuated several parameters of colitis as well expression of proinflammatory mediators in the colonic mucosa. In silico search coupled with qPCR identified AFTPH as a downstream target of miR-133α, while NT decreased AFTPH expression in NCM-460-NTR1 colonocytes. Gene silencing of AFTPH enhanced NT-induced proinflammatory responses and AFTPH levels were downregulated in experimental colitis. Levels of miR-133α were significantly upregulated, while AFTPH levels were downregulated in colonic biopsies of patients with ulcerative colitis compared to controls.
  
  
  CONCLUSIONS
  NT-associated colitis and inflammatory signalling are regulated by miR-133α-AFTPH interactions. Targeting of miR-133α or AFTPH may represent a novel therapeutic approach in inflammatory bowel disease.
authors.affiliation: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
authors.forename: Ivy Ka Man
authors.initials: IK
authors.lastname: Law
authors.affiliation: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Bakirtzi
authors.affiliation: Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
authors.forename: Christos
authors.initials: C
authors.lastname: Polytarchou
authors.affiliation: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
authors.forename: Angelos
authors.initials: A
authors.lastname: Oikonomopoulos
authors.affiliation: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hommes
authors.affiliation: Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Iliopoulos
authors.affiliation: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
mesh_terms: D000818:Animals; D003092:Colitis / Q000503:physiopathology*; D003106:Colon / Q000166:cytology / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs; D016328:NF-kappa B / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000502:physiology; D018028:Receptors, Neurotensin / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D035683:MicroRNAs; C517732:Mirn133 microRNA, mouse; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor
keywords: COLONIC DISEASES; EXPERIMENTAL COLITIS; IBD BASIC RESEARCH
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