Immunology. 2017 Mar;150(3):356-363. doi: 10.1111/imm.12690. Epub 2016 Dec 12.
High Smad7 sustains inflammatory cytokine response in refractory coeliac disease.
Sedda S1, De Simone V1, Marafini I1, Bevivino G1, Izzo R1, Paoluzi OA1, Colantoni A1, Ortenzi A1, Giuffrida P2, Corazza GR2, Vanoli A3, Di Sabatino A2, Pallone F1, Monteleone G1.
Abstract
Refractory
coeliac disease (RCD) is a form of coeliac disease (CD) resistant to
gluten-free diet and associated with elevated risk of complications.
Many effector cytokines over-produced in the gut of patients with RCD
are supposed to amplify the tissue-destructive immune response, but it
remains unclear if the RCD-associated mucosal inflammation is sustained
by defects in counter-regulatory mechanisms. The aim of the present
study was to determine whether RCD-related inflammation is marked by
high Smad7, an intracellular inhibitor of transforming growth factor-β1 (TGF-β1
) activity. Smad7 was evaluated in duodenal biopsy samples of patients
with RCD, patients with active CD, patients with inactive CD and healthy
controls by Western blotting, immunohistochemistry and real-time PCR.
In the same samples, TGF-β1 and phosphorylated (p)-Smad2/3
were evaluated by ELISA and immunohistochemistry, respectively.
Pro-inflammatory cytokine expression was evaluated in RCD samples
cultured with Smad7 sense or antisense oligonucleotide. Smad7 protein,
but not RNA, expression was increased in RCD compared with active and
inactive CD patients and healthy controls and this was associated with
defective TGF-β1 signalling, as marked by diminished p-Smad2/3 expression. TGF-β1
protein content did not differ among groups. Knockdown of Smad7 in RCD
biopsy samples reduced interleukin-6 and tumour necrosis factor-α
expression. In conclusion, in RCD, high Smad7 associates with defective
TGF-β1 signalling and sustains inflammatory cytokine
production. These results indicate a novel mechanism by which the
mucosal cytokine response is amplified in RCD and suggest that targeting
Smad7 can be therapeutically useful in RCD.
KEYWORDS:
gluten; inflammation; mucosal immune response; transforming growth factor-β
gluten; inflammation; mucosal immune response; transforming growth factor-β
- PMID:
- 27861825
- PMCID:
- PMC5290231
- [Available on 2018-03-01]
- DOI:
- 10.1111/imm.12690
- [Indexed for MEDLINE]
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