TGF-beta1 and Smad7 in the regulation of IBD.
Inflammatory bowel diseases (IBDs) are caused by an aberrant and excessive local immune response to components of the bacterial microflora that are: poorly controlled by endogenous counter regulatory mechanisms such as the immunosuppressive cytokine transforming growth factor-beta1 (TGF-beta1). Studies in human IBD tissues have documented a disruption of TGF-beta1 signaling marked by a block in the phosphorylation of the activated TGF-beta receptor-associated signaling molecule, Smad3, caused by the upregulation of the intracellular inhibitor of Smad signaling, Smad7. Inhibition of Smad7 with a specific antisense oligonucleotide restores TGF-beta1/Smad3 signaling, resulting in a marked suppression of inflammatory cytokine production. The functional relevance of Smad7 in gut inflammation was confirmed by studies in murine models of IBD. In inflamed tissues of mice with colitis induced by either the trinitrobenzene sulfonic acid or oxazolone, p-Smad3 was low despite active TGF-beta1 being produced in excess. In vivo administration of Smad7 antisense oligonucleotides to mice with colitis restored TGF-beta1 signaling and decreased the synthesis of inflammatory molecules and the extent of gut damage. These data support a role for Smad7 in maintaining intestinal inflammation, and suggest that blocking Smad7 could be a promising way to dampen the ongoing inflammation in IBD.
Monteleone
G
G
Department of Internal Medicine, University Tor Vergata of Rome, Rome, Italy. Gi.Monteleone@Med.uniroma2.it
Boirivant
M
M
Pallone
F
F
MacDonald
T T
TT
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D015398:Signal Transduction / Q000276:immunology; D051906:Smad7 Protein / Q000276:immunology* / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000276:immunology* / Q000378:metabolism*
D015415:Biomarkers; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1