Background & Aims: Defective transforming growth factor (TGF)-β1 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-β1 by enzyme-linked immunosorbent assay. The effect of oral Smad7 antisense oligonucleotide on mucosal inflammation was assessed. Results: TGF-β1 levels were increased in the inflamed tissues of mice with colitis induced by either TNBS or oxazolone. Nevertheless, TGF-β1 did not exert a regulatory effect, probably because TGF-β1 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-β1 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-β1 levels and defective TGF-β1 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. © 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-β1-Mediated Suppression of Colitis. GASTROENTEROLOGY, 131(6), 1786-1798 [10.1053/j.gastro.2006.09.016].

Inhibition of Smad7 With a Specific Antisense Oligonucleotide Facilitates TGF-β1-Mediated Suppression of Colitis

PALLONE, FRANCESCO;MONTELEONE, IVAN;PALMIERI, GIAMPIERO;MONTELEONE, GIOVANNI
2006-01-01

Abstract

Background & Aims: Defective transforming growth factor (TGF)-β1 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-β1 by enzyme-linked immunosorbent assay. The effect of oral Smad7 antisense oligonucleotide on mucosal inflammation was assessed. Results: TGF-β1 levels were increased in the inflamed tissues of mice with colitis induced by either TNBS or oxazolone. Nevertheless, TGF-β1 did not exert a regulatory effect, probably because TGF-β1 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-β1 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-β1 levels and defective TGF-β1 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. © 2006 AGA Institute.
2006
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/12 - GASTROENTEROLOGIA
English
antisense oligonucleotide; hapten; oxazolone; Smad3 protein; Smad7 protein; transforming growth factor beta1; trinitrobenzenesulfonic acid; animal experiment; animal model; animal tissue; article; colitis; controlled study; disease model; down regulation; drug effect; drug efficacy; enzyme linked immunosorbent assay; male; mouse; nonhuman; priority journal; protein expression; protein function; signal transduction; single drug dose; T lymphocyte; treatment outcome; Western blotting; Animals; Colitis; Disease Models, Animal; Down-Regulation; Female; Gene Expression Regulation; Male; Mice; Mice, Inbred BALB C; Mice, SCID; Oligonucleotides, Antisense; Signal Transduction; Smad3 Protein; Smad7 Protein; Transforming Growth Factor beta1; Trinitrobenzenesulfonic Acid
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-β1-Mediated Suppression of Colitis. GASTROENTEROLOGY, 131(6), 1786-1798 [10.1053/j.gastro.2006.09.016].
Boirivant, M; Pallone, F; Di Giacinto, C; Fina, D; Monteleone, I; Marinaro, M; Caruso, R; Colantoni, A; Palmieri, G; Sanchez, M; Strober, W; Macdonald...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/28809
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