title: MiR-155 modulates the inflammatory phenotype of intestinal myofibroblasts by targeting SOCS1 in ulcerative colitis.
abstract: Abnormal levels of microRNA (miR)-155, which regulate inflammation and immune responses, have been demonstrated in the colonic mucosa of patients with inflammatory bowel diseases (IBD), although its role in disease pathophysiology is unknown. We investigated the role of miR-155 in the acquisition and maintenance of an activated phenotype by intestinal myofibroblasts (IMF), a key cell population contributing to mucosal damage in IBD. IMF were isolated from colonic biopsies of healthy controls, ulcerative colitis (UC) and Crohn's disease (CD) patients. MiR-155 in IMF was quantified by quantitative reverse transcription-PCR in basal condition and following exposure to TNF-α, interleukin (IL)-1β, lipopolysaccharide (LPS) or TGF-β1. The effects of miR-155 mimic or inhibitor transfection on cytokine release and suppressor of cytokine signaling 1 (SOCS1) expression were assessed by enzyme-linked immunosorbent assay and western blot, respectively. Regulation of the target gene SOCS1 expression by miR-155 was assessed using luciferase reporter construct. We found that miR-155 was significantly upregulated in UC as compared with control- and CD-derived IMF. Moreover, TNF-α and LPS, but not TGF-β1 and IL-1β, significantly increased miR-155 expression in IMF. Ectopic expression of miR-155 in control IMF augmented cytokines release, whereas it downregulated SOCS1 expression. MiR-155 knockdown in UC-IMF reduced cytokine production and enhanced SOCS1 expression. Luciferase reporter assay demonstrated that miR-155 directly targets SOCS1. Moreover, silencing of SOCS1 in control IMF significantly increased IL-6 and IL-8 release. In all, our data suggest that inflammatory mediators induce miR-155 expression in IMF of patients with UC. By downregulating the expression of SOCS1, miR-155 wires IMF inflammatory phenotype.
authors.affiliation: 1] Department of Surgery Oncology and Gastroenterology DISCOG, University of Padova, Padova, Italy [2] Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Surajit
authors.initials: S
authors.lastname: Pathak
authors.affiliation: 1] Department of Surgery Oncology and Gastroenterology DISCOG, University of Padova, Padova, Italy [2] Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Alessia Rosaria
authors.initials: AR
authors.lastname: Grillo
authors.affiliation: Oncological Surgery Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy.
authors.forename: Melania
authors.initials: M
authors.lastname: Scarpa
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Brun
authors.affiliation: Department of Surgery Oncology and Gastroenterology DISCOG, University of Padova, Padova, Italy.
authors.forename: Renata
authors.initials: R
authors.lastname: D'Incà
authors.affiliation: 1] Department of Surgery Oncology and Gastroenterology DISCOG, University of Padova, Padova, Italy [2] Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Nai
authors.affiliation: Department of Surgery Oncology and Gastroenterology DISCOG, University of Padova, Padova, Italy.
authors.forename: Antara
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Cavallo
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Barzon
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
authors.affiliation: Department of Surgery Oncology and Gastroenterology DISCOG, University of Padova, Padova, Italy.
authors.forename: Giacomo Carlo
authors.initials: GC
authors.lastname: Sturniolo
authors.affiliation: Department of Surgery Oncology and Gastroenterology DISCOG, University of Padova, Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Buda
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Ignazio
authors.initials: I
authors.lastname: Castagliuolo
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D016207:Cytokines / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D058628:Myofibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D016207:Cytokines; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha