Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 674-682 |
| Number of pages | 9 |
| Journal | Gastroenterology |
| Volume | 126 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 2004 |
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- Gastroenterology
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Induction and Regulation of Smad7 in the Gastric Mucosa of Patients with Helicobacter pylori Infection. / Monteleone, Giovanni; Del Vecchio Blanco, Giovanna; Palmieri, Giampiero; Vavassori, Piero; Monteleone, Ivan; Colantoni, Alfredo; Battista, Serena; Spagnoli, Luigi Giusto; Romano, Marco; Borrelli, Melissa; MacDonald, Thomas T.; Pallone, Francesco.
In: Gastroenterology, Vol. 126, No. 3, 03.2004, p. 674-682.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Induction and Regulation of Smad7 in the Gastric Mucosa of Patients with Helicobacter pylori Infection
AU - Monteleone, Giovanni
AU - Del Vecchio Blanco, Giovanna
AU - Palmieri, Giampiero
AU - Vavassori, Piero
AU - Monteleone, Ivan
AU - Colantoni, Alfredo
AU - Battista, Serena
AU - Spagnoli, Luigi Giusto
AU - Romano, Marco
AU - Borrelli, Melissa
AU - MacDonald, Thomas T.
AU - Pallone, Francesco
PY - 2004/3
Y1 - 2004/3
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=10744231157&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2003.11.048
DO - 10.1053/j.gastro.2003.11.048
M3 - Article
C2 - 14988821
AN - SCOPUS:10744231157
VL - 126
SP - 674
EP - 682
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 3
ER -