Knockdown of Smad7 With a Specific Antisense Oligonucleotide Attenuates Colitis and Colitis-Driven Colonic Fibrosis in Mice
| Autor: | Ivan Monteleone, Martina Di Giovangiulio, Roberta Izzo, Angela Ortenzi, Eleonora Franzè, Irene Marafini, Alfredo Colantoni, Veronica De Simone, Angelamaria Rizzo, Gerolamo Bevivino, Giovanni Monteleone, Silvia Sedda |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Colon Oligonucleotides Down-Regulation Pharmacology Peripheral blood mononuclear cell Collagen Type I Smad7 Protein Transforming Growth Factor beta1 Mice 03 medical and health sciences 0302 clinical medicine Immune system Crohn Disease Downregulation and upregulation Fibrosis medicine Animals Immunology and Allergy Smad3 Protein Colitis Mice Inbred BALB C Lamina propria Gene knockdown integumentary system business.industry Gastroenterology Oligonucleotides Antisense medicine.disease Disease Models Animal 030104 developmental biology medicine.anatomical_structure Trinitrobenzenesulfonic Acid Gene Knockdown Techniques 030220 oncology & carcinogenesis Immunohistochemistry Female business Signal Transduction |
| Zdroj: | Inflammatory Bowel Diseases. 24:1213-1224 |
| ISSN: | 1536-4844 1078-0998 |
| DOI: | 10.1093/ibd/izy062 |
| Popis: | Background In Crohn's disease (CD), the pathogenic immune response is associated with high Smad7, an inhibitor of TGF-β1 signaling. Smad7 knockdown with Mongersen, a specific antisense oligonucleotide-containing compound, restores TGF-β1 activity leading to inhibition of inflammatory signals and associates with clinical benefit in CD patients. As TGF-β1 is pro-fibrogenic, it remains unclear whether Mongersen-induced Smad7 inhibition increases the risk of intestinal fibrosis. We assessed the impact of Smad7 inhibition on the course of colitis-driven intestinal fibrosis in mice. Methods BALB/c mice were rectally treated with increasing doses of trinitrobenzene sulfonic acid (TNBS) for 8 or 12 weeks. The effect of oral Smad7 antisense or control oligonucleotide, administered to mice starting from week 5 or week 8, respectively, on mucosal inflammation and colitis-associated colonic fibrosis was assessed. Mucosal samples were analyzed for Smad7 by immunoblotting and immunohistochemistry, TGF-β1 by enzyme-linked immunosorbent assay, and collagen by immunohistochemistry. Results TNBS-induced chronic colitis was associated with colonic deposition of collagen I and fibrosis, which were evident at week 8 and became more pronounced at week 12. TNBS treatment enhanced Smad7 in both colonic epithelial and lamina propria mononuclear cells. Colitic mice treated with Smad7 antisense oligonucleotide exhibited reduced signs of colitis, less collagen deposition, and diminished fibrosis. These findings were associated with diminished synthesis of TGF-β1 and reduced p-Smad3 protein expression. Conclusion Attenuation of colitis with Smad7 antisense oligonucleotide limits development of colonic fibrosis. |
| Databáze: | OpenAIRE |
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