Induction and Regulation of Smad7 in the Gastric Mucosa of Patients with Helicobacter pylori Infection

Giovanni Monteleone, Giovanna Del Vecchio Blanco, Giampiero Palmieri, Piero Vavassori, Ivan Monteleone, Alfredo Colantoni, Serena Battista, Luigi Giusto Spagnoli, Marco Romano, Melissa Borrelli, Thomas T. MacDonald, Francesco Pallone

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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 languageEnglish
Pages (from-to)674-682
Number of pages9
JournalGastroenterology
Volume126
Issue number3
DOIs
Publication statusPublished - Mar 2004

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Helicobacter Infections
Gastric Mucosa
Helicobacter pylori
Transforming Growth Factors
Interferons
Biopsy
Stomach
Gastritis
Th1 Cells
Antisense Oligonucleotides
Digestion
Mucous Membrane
Western Blotting
Enzyme-Linked Immunosorbent Assay
Phosphorylation
Cytokines
Inflammation

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Monteleone, G., Del Vecchio Blanco, G., Palmieri, G., Vavassori, P., Monteleone, I., Colantoni, A., ... Pallone, F. (2004). Induction and Regulation of Smad7 in the Gastric Mucosa of Patients with Helicobacter pylori Infection. Gastroenterology, 126(3), 674-682. https://doi.org/10.1053/j.gastro.2003.11.048

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 journalArticle

Monteleone, G, Del Vecchio Blanco, G, Palmieri, G, Vavassori, P, Monteleone, I, Colantoni, A, Battista, S, Spagnoli, LG, Romano, M, Borrelli, M, MacDonald, TT & Pallone, F 2004, 'Induction and Regulation of Smad7 in the Gastric Mucosa of Patients with Helicobacter pylori Infection', Gastroenterology, vol. 126, no. 3, pp. 674-682. https://doi.org/10.1053/j.gastro.2003.11.048
Monteleone G, Del Vecchio Blanco G, Palmieri G, Vavassori P, Monteleone I, Colantoni A et al. Induction and Regulation of Smad7 in the Gastric Mucosa of Patients with Helicobacter pylori Infection. Gastroenterology. 2004 Mar;126(3):674-682. https://doi.org/10.1053/j.gastro.2003.11.048
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. / Induction and Regulation of Smad7 in the Gastric Mucosa of Patients with Helicobacter pylori Infection. In: Gastroenterology. 2004 ; Vol. 126, No. 3. pp. 674-682.
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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

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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.

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