Induction and regulation of Smad7 in the gastric mucosa of patients with Helicobacter pylori infection.
OBJECTIVE
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.
Department of Internal Medicine and Center for Excellence for Genomic Risk Assessment in Multifactorial and Complex Diseases, University Tor Vergata, Rome, Italy. Gi.Monteleone@Med.uniroma2.it
Giovanni
G
Monteleone
Giovanna
G
Del Vecchio Blanco
Giampiero
G
Palmieri
Piero
P
Vavassori
Ivan
I
Monteleone
Alfredo
A
Colantoni
Serena
S
Battista
Luigi Giusto
LG
Spagnoli
Marco
M
Romano
Melissa
M
Borrelli
Thomas T
TT
MacDonald
Francesco
F
Pallone
D000328:Adult; D000368:Aged; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D005786:Gene Expression Regulation; D016481:Helicobacter Infections / Q000235:genetics / Q000378:metabolism*; D016480:Helicobacter pylori; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009924:Organ Culture Techniques; D010766:Phosphorylation; D015398:Signal Transduction; D051900:Smad3 Protein; D051906:Smad7 Protein; D020825:T-Box Domain Proteins; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D000098815:T-bet Transcription Factor
D004268:DNA-Binding Proteins; C497790:SMAD3 protein, human; C497806:SMAD7 protein, human; D051900:Smad3 Protein; D051906:Smad7 Protein; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C508960:TGFB1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma