Background & Aims: Defective transforming growth factor (TGF)-Î²1 signaling due to high levels of Smad7 is a feature of inflammatory bowel disease (IBD). In this study, we analyzed the effect of reducing Smad7 levels with antisense oligonucleotide on mouse models of colitis. Methods: Mucosal samples taken from colitic tissue of mice with colitis due to either haptenating reagents (trinitrobenzene sulfonic acid [TNBS] or oxazolone) or to transfer of T cells (SCID transfer colitis) were analyzed for Smad3 and/or Smad7 expression by Western blotting and, in some cases, content of TGF-Î²1 by enzyme-linked immunosorbent assay. The effect of oral Smad7 antisense oligonucleotide on mucosal inflammation was assessed. Results: TGF-Î²1 levels were increased in the inflamed tissues of mice with colitis induced by either TNBS or oxazolone. Nevertheless, TGF-Î²1 did not exert a regulatory effect, probably because TGF-Î²1 signaling was blocked, as indicated by the presence of reduced Smad3 phosphorylation and high levels of Smad7. Oral administration of Smad7 antisense oligonucleotide to colitic mice restored TGF-Î²1 signaling via Smad3 and ameliorated inflammation in hapten-induced colitis. In addition, Smad7 antisense oligonucleotide had a therapeutic effect on relapsing TNBS-induced colitis but not on cell-transfer colitis. Conclusions: These data suggest that colitis models associated with high endogenous TGF-Î²1 levels and defective TGF-Î²1 signaling due to high levels of Smad7 can be ameliorated by down-regulation of Smad7 and by oral administration of Smad7 antisense oligonucleotide. This may represent a new approach to the control of IBD, particularly during active phases when its Smad7 profile resembles that of hapten-induced colitis. Â© 2006 AGA Institute.
Boirivant, M., Pallone, F., Di Giacinto, C., Fina, D., Monteleone, I., Marinaro, M., et al. (2006). Inhibition of Smad7 With a Specific Antisense Oligonucleotide Facilitates TGF-Î²1-Mediated Suppression of Colitis. GASTROENTEROLOGY, 131(6), 1786-1798.
|Tipologia:||Articolo su rivista|
|Citazione:||Boirivant, M., Pallone, F., Di Giacinto, C., Fina, D., Monteleone, I., Marinaro, M., et al. (2006). Inhibition of Smad7 With a Specific Antisense Oligonucleotide Facilitates TGF-Î²1-Mediated Suppression of Colitis. GASTROENTEROLOGY, 131(6), 1786-1798.|
|Settore Scientifico Disciplinare:||Settore MED/12 - Gastroenterologia|
|Revisione (peer review):||Sì, ma tipo non specificato|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1053/j.gastro.2006.09.016|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2006|
|Titolo:||Inhibition of Smad7 With a Specific Antisense Oligonucleotide Facilitates TGF-Î²1-Mediated Suppression of Colitis|
|Autori:||Boirivant, M; Pallone, F; Di Giacinto, C; Fina, D; Monteleone, I; Marinaro, M; Caruso, R; Colantoni, A; Palmieri, G; Sanchez, M; Strober, W; MacDonald, T; Monteleone, G|
|Appare nelle tipologie:||01 - Articolo su rivista|