Induction and regulation of Smad7 in the gastric mucosa of patients with Helicobacter pylori infection
Background & Aims : Helicobacter pylori ( Hp) infection causes a chronic gastric inflammation, which can lead to peptic ulceration and cancer. The inflammatory response is multifactorial and is characterized by exaggerated Th1 cytokine production. How the Th1 response is induced and maintained i...
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Veröffentlicht in: | Gastroenterology (New York, N.Y. 1943) N.Y. 1943), 2004-03, Vol.126 (3), p.674-682 |
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Sprache: | eng |
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Zusammenfassung: | Background & Aims
:
Helicobacter pylori (
Hp) infection causes a chronic gastric inflammation, which can lead to peptic ulceration and cancer. The inflammatory response is multifactorial and is characterized by exaggerated Th1 cytokine production. How the Th1 response is induced and maintained in the stomach of
Hp-infected patients remains unclear. Transforming growth factor (TGF)-β1 negatively regulates Th1 cell development, and TGF-β1-deficient mice spontaneously develop gastritis. Here, we examined TGF-β1 signaling in
Hp-associated gastritis.
Methods
:
Gastric biopsy specimens taken from patients with or without
Hp infection were analyzed for the content of activated TGF-β1 by ELISA and Smad3 and 7 expression by Western blotting. Induction of Smad7 by interferon (IFN)-γ was examined in normal gastric mucosal biopsy specimens, whereas the effect of Smad7 inhibition on the ongoing Th1 response was analyzed in
Hp-colonized biopsy specimens.
Results
:
Activated TGF-β1 was abundant in the mucosa of controls and
Hp-infected patients, with no significant difference between the 2 groups. Despite this, in whole biopsy specimens and isolated mucosal cells from
Hp-infected patients, there was defective TGF-β1-associated Smad3 phosphorylation, which was associated with high expression of the inhibitor Smad7. Blocking Smad7 with antisense oligonucleotides restored TGF-β1 signaling in biopsy specimens from
Hp-infected patients and concomitantly reduced interferon-γ and T-bet. Smad7 was inducible in normal gastric biopsy specimens by interferon-γ through a STAT1-dependent mechanism, and neutralization of interferon-γ in biopsy specimens from
Hp-infected patients reduced Smad7 expression.
Conclusions
:
These data suggest that, in
Hp-infected gastric mucosa, interferon-γ induces the expression of Smad7, which then prevents endogenous TGF-β1 from down-regulating the ongoing tissue-damaging Th1 response. |
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ISSN: | 0016-5085 1528-0012 |
DOI: | 10.1053/j.gastro.2003.11.048 |