Blocking Smad7 restores TGF-β1 signaling in chronic inflammatory bowel disease

Monteleone, Giovanni; Kumberová, Andrea; Croft, Nicholas M.; McKenzie, Catriona; Steer, H W; MacDonald, Thomas T.

doi:10.1172/jci12821

Cited by 537 publications

(294 citation statements)

References 29 publications

Supporting

Mentioning

273

Contrasting

Unclassified

Order By: Relevance

“…A diminished response to TGF-β1 is seen in mice with deficient Smad3 which are at increased risk of developing chronic inflammation of the colon [51]. Active Smad3 is decreased in both CD and UC [52]. Smad7, on the other hand, inhibits Smad2 and 3 [50] in addition to promoting the ubiquitin degradation process of TGF-β1 [53], which renders TGF-β1 a proinflammatory molecule (fig.…”

Section: Smad7 Anti-sensementioning

confidence: 99%

“…In mouse models of colitis, there is a marked increase in TGF-β1 production in light of reduced active pSmad3 and high Smad7 activity [54]. Interestingly, Smad7 is overexpressed in CD and UC, and its silencing with an antisense nucleotide or in Smad7 knockdown models was able to reestablish the anti-inflammatory response of TGF-β1 [52]. When anti-Smad7 oligonucleotide was administered, a decrease in the severity of colitis was observed in parallel to a restoration of TGF-β1 and its anti-inflammatory response [54].…”

Section: Smad7 Anti-sensementioning

confidence: 99%

See 1 more Smart Citation

New and Evolving Immunotherapy in Inflammatory Bowel Disease

2016

View full text Add to dashboard Cite

Background: Crohn's disease and ulcerative colitis are chronic inflammatory disorders associated with a dysregulated adaptive and innate immune response to gut commensals in genetically susceptible individuals. The pathogenesis of inflammatory bowel disease is complex, and the disease is characterized by significant phenotypic and genotypic heterogeneity. Summary: The introduction of anti-TNF biologics has resulted in improved clinical outcomes in patients with severe and moderately severe disease, but the current treatment paradigm continues to depend on systemic immunosuppression (steroids and immunomodulators) and surgical intervention in a significant number of patients, underscoring a significant unmet need. More recently, a number of genetic and immunologic abnormalities have been unraveled including aberrant intestinal mucosal defense function, abnormal intestinal permeability, dysregulated bacterial antigen processing by macrophages and presentation to T cells, cellular immune regulation and signaling, cytokine production, and leukocyte trafficking. Key Messages: Understanding these molecular mechanisms and effector pathways presents an opportunity for the development of new and improved targeted therapies.

show abstract

Section: Smad7 Anti-sensementioning

confidence: 99%

Section: Smad7 Anti-sensementioning

confidence: 99%

New and Evolving Immunotherapy in Inflammatory Bowel Disease

2016

View full text Add to dashboard Cite

show abstract

“…We recently documented a defective TGF-β1-associated Smad3 phosphorylation in the gut of patients with CD and UC [48]. This finding was associated with high Smad7, an inhibitor Smad7 that binds to the TGF-β1RI and prevents the phosphorylation of Smad3 (Fig.…”

Section: Immune System Fails To Negatively Regulate the Ongoing Inflamentioning

confidence: 93%

Genetic and pathogenetic insights into inflammatory bowel disease

Pallone

Blanco

Vavassori

et al. 2003

Curr Gastroenterol Rep

Self Cite

View full text Add to dashboard Cite

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract that share clinical and pathologic characteristics. The most credible hypothesis is that CD and UC result from an inappropriate and exaggerated mucosal immune response to normal constituents of the mucosal microflora that is in part genetically determined. However, there is reason to believe that the main pathologic processes in these two diseases are distinct. For example, the CARD15/NOD2 gene has been identified as a susceptibility gene for CD but not for UC. Moreover, the study of patients and mouse models of inflammatory bowel disease has clearly shown that, in CD, the tissue-damaging inflammatory reaction is driven by interleukin-12-activated Th1 cells, whereas a humoral response predominates in UC.

show abstract

“…That is, it was observed that phosphorylation of the R-Smad, Smad3, was inhibited, whereas Smad7-an inhibitory Smad-was overexpressed in the intestinal mucosa of IBD patients. 62 It has been suggested that this disruption of the TGF-pathway might lead to the excessive production of IFN-γ and TNF-α that is associated with chronic inflammation in the local mucosa. 63,64 …”

Section: Tgf-signaling and Inflammatory Bowel Diseasementioning

confidence: 99%