title: The TGF-β/Smad System in IBD Pathogenesis.
abstract: In Crohn's disease and ulcerative colitis, the tissue-damaging destructive immune response is sustained by defects of counterregulatory mechanisms, which normally attenuate inflammatory pathways and promote repair of mucosal injury. One such mechanism involves transforming growth factor-β1 (TGF-β1), a cytokine that is produced by multiple cell types and targets both immune and nonimmune cells. Both in vitro and in vivo studies strongly support the role of TGF-β1 as a negative regulator of mucosal inflammation and indicate that defective production/activity of this cytokine can lead to the development of or exacerbate colitis. Interestingly, in the inflamed intestine of patients with inflammatory bowel disease, TGF-β1 expression is upregulated but TGF-β1-mediated immunosuppression is markedly impaired because of high Smad7, an intracellular inhibitor of TGF-β1-associated signaling. Consistently, knockdown of Smad7 with a specific antisense oligonucleotide restores TGF-β1 activity, thus leading to decreased production of inflammatory cytokines in both colitic mice and inflammatory bowel disease patients and attenuates clinical activity in Crohn's disease patients. In this article, we review data supporting the role of Smad7 in the pathogenesis of inflammatory bowel disease and discuss whether inhibition of Smad7 is therapeutically useful in Crohn's disease and how the benefit/risk of such an intervention should be monitored in the patients.
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sedda
authors.forename: Irene
authors.initials: I
authors.lastname: Marafini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Dinallo
authors.forename: Davide
authors.initials: D
authors.lastname: Di Fusco
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D000818:Animals; D003092:Colitis / Q000276:immunology / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000276:immunology / Q000378:metabolism*; D003424:Crohn Disease / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D015398:Signal Transduction; D051906:Smad7 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1