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Inhibition of Smad7 with a specific antisense oligonucleotide facilitates TGF-beta1-mediated suppression of colitis.
- Source :
-
Gastroenterology [Gastroenterology] 2006 Dec; Vol. 131 (6), pp. 1786-98. Date of Electronic Publication: 2006 Sep 19. - Publication Year :
- 2006
-
Abstract
- Background & Aims: Defective transforming growth factor (TGF)-beta1 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.<br />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-beta1 by enzyme-linked immunosorbent assay. The effect of oral Smad7 antisense oligonucleotide on mucosal inflammation was assessed.<br />Results: TGF-beta1 levels were increased in the inflamed tissues of mice with colitis induced by either TNBS or oxazolone. Nevertheless, TGF-beta1 did not exert a regulatory effect, probably because TGF-beta1 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-beta1 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.<br />Conclusions: These data suggest that colitis models associated with high endogenous TGF-beta1 levels and defective TGF-beta1 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.
- Subjects :
- Animals
Colitis chemically induced
Colitis genetics
Disease Models, Animal
Down-Regulation
Female
Gene Expression Regulation drug effects
Male
Mice
Mice, Inbred BALB C
Mice, SCID
Oligonucleotides, Antisense therapeutic use
Signal Transduction genetics
Smad3 Protein genetics
Smad3 Protein metabolism
Smad7 Protein genetics
Transforming Growth Factor beta1 genetics
Trinitrobenzenesulfonic Acid
Colitis metabolism
Colitis prevention & control
Oligonucleotides, Antisense pharmacology
Smad7 Protein metabolism
Transforming Growth Factor beta1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0016-5085
- Volume :
- 131
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 17087939
- Full Text :
- https://doi.org/10.1053/j.gastro.2006.09.016