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)-beta 1 negatively regulates Th1 cell development, and TGF-beta 1-deficient mice spontaneously develop gastritis. Here, we examined TGF-beta 1 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-beta1 by ELISA and Smad3 and 7 expression by Western blotting. Induction of Smad7 by interferon (IFN)-gamma 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-beta 1 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-beta 1-associated Smad3 phosphorylation, which was associated with high expression of the inhibitor Smad7. Blocking Smad7 with antisense oligonucleotides restored TGF-beta 1 signaling in biopsy specimens from Hp-infected patients and concomitantly reduced interferon-gamma and T-bet. Smad7 was inducible in normal gastric biopsy specimens by interferon-gamma through a STAT1-dependent mechanism, and neutralization of interferon-gamma in biopsy specimens from Hp-infected patients reduced Smad7 expression. CONCLUSIONS: These data suggest that, in Hp-infected gastric mucosa, interferon-gamma induces the expression of Smad7, which then prevents endogenous TGF-beta 1 from down-regulating the ongoing tissue-damaging Th1 response.
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-infectedpatients remains unclear. Transforming growth factor (TGF)-beta 1 negatively regulates Th1 cell development, and TGF-beta 1-deficient mice spontaneously develop gastritis. Here, we examined TGF-beta 1 signaling in Hp-associated gastritis. METHODS: Gastric biopsy specimens taken from patients with or without Hpinfection were analyzed for the content of activated TGF-beta1 by ELISA and Smad3 and 7 expression by Western blotting. Induction of Smad7 by interferon (IFN)-gamma 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-beta 1 was abundant in the mucosa of controls and Hp-infectedpatients, with no significant difference between the 2 groups. Despite this, in whole biopsy specimens and isolated mucosal cells from Hp-infectedpatients, there was defective TGF-beta 1-associated Smad3 phosphorylation, which was associated with high expression of the inhibitor Smad7. Blocking Smad7 with antisense oligonucleotides restored TGF-beta 1 signaling in biopsy specimens from Hp-infectedpatients and concomitantly reduced interferon-gamma and T-bet. Smad7 was inducible in normal gastric biopsy specimens by interferon-gamma through a STAT1-dependent mechanism, and neutralization of interferon-gamma in biopsy specimens from Hp-infectedpatients reduced Smad7 expression. CONCLUSIONS: These data suggest that, in Hp-infected gastric mucosa, interferon-gamma induces the expression of Smad7, which then prevents endogenous TGF-beta 1 from down-regulating the ongoing tissue-damaging Th1 response.
Authors: Omero Alessandro Paoluzi; Del Vecchio Giovanna Blanco; Roberta Caruso; Ivan Monteleone; Giovanni Monteleone; Francesco Pallone Journal: World J Gastroenterol Date: 2014-01-21 Impact factor: 5.742
Authors: Matthias Ernst; Meri Najdovska; Dianne Grail; Therese Lundgren-May; Michael Buchert; Hazel Tye; Vance B Matthews; Jane Armes; Prithi S Bhathal; Norman R Hughes; Eric G Marcusson; James G Karras; Songqing Na; Jonathon D Sedgwick; Paul J Hertzog; Brendan J Jenkins Journal: J Clin Invest Date: 2008-05 Impact factor: 14.808
Authors: B Gurram; N H Salzman; M L Kaldunski; S Jia; B U K Li; M Stephens; M R Sood; M J Hessner Journal: Clin Exp Immunol Date: 2016-01-29 Impact factor: 4.330