Clinical-alimentary tractInduction and regulation of Smad7 in the gastric mucosa of patients with Helicobacter pylori infection☆
Section snippets
Patients and sampling
Sixty-five patients (33 men and 32 women; median age, 49 years; range, 21–74 years) who underwent esophagogastroduodenoscopy for dyspeptic symptoms were studied. Thirty-three patients had Hp infection as confirmed by urease quick test and histology. Five Hp-infected patients were reendoscoped 2 months after cessation of 1-week treatment with omeprazole (20 mg twice daily), amoxycillin (1000 mg twice daily), and clarithromycin (500 mg twice daily). All these 5 patients were cured of Hp infection
Activated TGF-β1 is produced in the human gastric mucosa
TGF-β1 negatively regulates mucosal immune responses, and defects in TGF-β1 production have been associated with the development of gastritis in experimental models.9, 10, 11, 12 Therefore, we first sought to analyze whether the Hp-related gastritis associates with changes in the local concentrations of activated TGF-β1. Because several gastric mucosal cell types have the potential to synthesize TGF-β1, the cytokine was measured in total proteins extracted from whole gastric mucosa rather than
Discussion
In this study, we show that colonization of the stomach with Hp leads to a reduction in Smad3 phosphorylation, a crucial step in the TGF-β1-mediated signal transduction, despite the synthesis of active TGF-β1. The failure in TGF-β1 signaling is associated with high expression of Smad7, an inhibitor of TGF-β1-associated Smad3 phosphorylation. In contrast, abundant phosphorylated Smad3 is seen in the normal gastric mucosa, consistent with constitutively active TGF-β1 signaling.
TGF-β1 is one of
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SMAD proteins: Mediators of diverse outcomes during infection
2022, European Journal of Cell BiologyCitation Excerpt :Colonising more than half the global population, H. pylori is linked with gastritis, intestinal metaplasia, and gastric carcinoma (Monteleone et al., 2004; Shuang et al., 2015). H. pylori infection of gastric epithelial cells results in activation of NFκB, secretion of IL-8, and a localised Th1 response with increased expression of IL-12, TNF-α and IFN-γ (Monteleone et al., 2004; Shuang et al., 2015). Since TGF-β is an antagonist to Th1 responses, SMAD7 overexpression is a potential mechanism by which TGF-β signalling is attenuated and its anti-inflammatory effects ablated during H. pylori infection (Fig. 3).
TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer
2021, GastroenterologyThe role of transforming growth factor (TGF)-β in modulating the immune response and fibrogenesis in the gut
2014, Cytokine and Growth Factor ReviewsCitation Excerpt :This is likely to derive from the restoration of endogenous TGF-β activity, as the ex vivo effects of the Smad7 antisense oligonucleotide are decreased by the addition of a TGF-β neutralizing antibody [105]. Elevated levels of Smad7 and impaired TGF-β1 signaling are not specific features of IBD, since the same alterations have been also observed in the gastric mucosa of patients with Helicobacter pylori infection [106]. Treg, while being reduced in peripheral blood of patients with active IBD, are increased in the inflamed intestinal mucosa of IBD patients [107,108].
Smad7 antisense oligonucleotide-based therapy for inflammatory bowel diseases
2013, Digestive and Liver DiseaseCitation Excerpt :In line with this was also the observation that treatment of mucosal explants from CD patients with Smad7 antisense oligonucleotide inhibited Smad7 protein, enhanced Smad3 phosphorylation and decreased inflammatory cytokine production, an effect which was partially blocked by a neutralising TGF-β1 antibody [15]. Up-regulation of Smad7 and diminished expression of phosphorylated Smad3 are not however a specific hallmark of IBD, because similar findings were seen in biopsies taken from Helicobacter pylori-infected patients [20]. By contrast, Smad7 is not up-regulated in the duodenum of patients with active celiac disease [21], suggesting that induction of Smad7 is not an epiphenomenon of the ongoing mucosal inflammation.
Smad7 protein induces interferon regulatory factor 1-dependent transcriptional activation of caspase 8 to restore tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis
2013, Journal of Biological ChemistryCitation Excerpt :Interestingly, halofuginone has recently been shown to inhibit tumor growth and metastasis through the blocking of angiogenesis and matrix metalloproteinase in various tumors (60, 61). It is well known that IFN-γ induces Smad7 through the Jak1/STAT pathway to block TGF-β signaling (30–32). Because cotreatment of IFN-γ and TRAIL synergistically induced the apoptosis in neuroblastoma cells and Ewing sarcoma, it will be interesting to examine the involvement of Smad7 in this effect based on our study (28, 29, 62).
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Supported by the Broad Medical Research Program Foundation.