High Smad7 sustains inflammatory cytokine response in refractory coeliac disease

S. Sedda, V. De Simone, I. Marafini, G. Bevivino, R. Izzo, O. A. Paoluzi, A. Colantoni, A. Ortenzi, P. Giuffrida, G. R. Corazza, A. Vanoli, A. Di Sabatino, F. Pallone, G. Monteleone

Research output: Contribution to journalArticle

2 Citations (Scopus)

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-beta1 (TGF-beta1 ) 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-beta1 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-beta1 signalling, as marked by diminished p-Smad2/3 expression. TGF-beta1 protein content did not differ among groups. Knockdown of Smad7 in RCD biopsy samples reduced interleukin-6 and tumour necrosis factor-alpha expression. In conclusion, in RCD, high Smad7 associates with defective TGF-beta1 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.
Original languageEnglish
Pages (from-to)356-363
Number of pages8
JournalImmunology
Volume150
Issue number3
DOIs
Publication statusPublished - Mar 1 2017

Fingerprint

Celiac Disease
Cytokines
Transforming Growth Factor beta1
Smad7 Protein
Immunohistochemistry
Inflammation
Biopsy
Gluten-Free Diet
Antisense Oligonucleotides
Real-Time Polymerase Chain Reaction
Interleukin-6

Keywords

  • Biopsy
  • Celiac Disease/immunology/therapy
  • Diet, Gluten-Free
  • Duodenum/immunology
  • Humans
  • Inflammation/immunology
  • Interleukin-6/metabolism
  • Intestinal Mucosa/immunology
  • Molecular Targeted Therapy
  • RNA, Small Interfering/genetics
  • Recurrence
  • Signal Transduction
  • Smad7 Protein/genetics/metabolism
  • Transforming Growth Factor beta/metabolism
  • Tumor Necrosis Factor-alpha/metabolism
  • gluten
  • inflammation
  • mucosal immune response
  • transforming growth factor-beta

Cite this

Sedda, S., Simone, V. D., Marafini, I., Bevivino, G., Izzo, R., Paoluzi, O. A., ... Monteleone, G. (2017). High Smad7 sustains inflammatory cytokine response in refractory coeliac disease. Immunology, 150(3), 356-363. https://doi.org/10.1111/imm.12690 [doi]

High Smad7 sustains inflammatory cytokine response in refractory coeliac disease. / Sedda, S.; Simone, V. De; Marafini, I.; Bevivino, G.; Izzo, R.; Paoluzi, O. A.; Colantoni, A.; Ortenzi, A.; Giuffrida, P.; Corazza, G. R.; Vanoli, A.; Sabatino, A. Di; Pallone, F.; Monteleone, G.

In: Immunology, Vol. 150, No. 3, 01.03.2017, p. 356-363.

Research output: Contribution to journalArticle

Sedda, S, Simone, VD, Marafini, I, Bevivino, G, Izzo, R, Paoluzi, OA, Colantoni, A, Ortenzi, A, Giuffrida, P, Corazza, GR, Vanoli, A, Sabatino, AD, Pallone, F & Monteleone, G 2017, 'High Smad7 sustains inflammatory cytokine response in refractory coeliac disease', Immunology, vol. 150, no. 3, pp. 356-363. https://doi.org/10.1111/imm.12690 [doi]
Sedda S, Simone VD, Marafini I, Bevivino G, Izzo R, Paoluzi OA et al. High Smad7 sustains inflammatory cytokine response in refractory coeliac disease. Immunology. 2017 Mar 1;150(3):356-363. https://doi.org/10.1111/imm.12690 [doi]
Sedda, S. ; Simone, V. De ; Marafini, I. ; Bevivino, G. ; Izzo, R. ; Paoluzi, O. A. ; Colantoni, A. ; Ortenzi, A. ; Giuffrida, P. ; Corazza, G. R. ; Vanoli, A. ; Sabatino, A. Di ; Pallone, F. ; Monteleone, G. / High Smad7 sustains inflammatory cytokine response in refractory coeliac disease. In: Immunology. 2017 ; Vol. 150, No. 3. pp. 356-363.
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AU - Sedda, S.

AU - Simone, V. De

AU - Marafini, I.

AU - Bevivino, G.

AU - Izzo, R.

AU - Paoluzi, O. A.

AU - Colantoni, A.

AU - Ortenzi, A.

AU - Giuffrida, P.

AU - Corazza, G. R.

AU - Vanoli, A.

AU - Sabatino, A. Di

AU - Pallone, F.

AU - Monteleone, G.

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N2 - 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-beta1 (TGF-beta1 ) 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-beta1 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-beta1 signalling, as marked by diminished p-Smad2/3 expression. TGF-beta1 protein content did not differ among groups. Knockdown of Smad7 in RCD biopsy samples reduced interleukin-6 and tumour necrosis factor-alpha expression. In conclusion, in RCD, high Smad7 associates with defective TGF-beta1 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.

AB - 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-beta1 (TGF-beta1 ) 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-beta1 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-beta1 signalling, as marked by diminished p-Smad2/3 expression. TGF-beta1 protein content did not differ among groups. Knockdown of Smad7 in RCD biopsy samples reduced interleukin-6 and tumour necrosis factor-alpha expression. In conclusion, in RCD, high Smad7 associates with defective TGF-beta1 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.

KW - Biopsy

KW - Celiac Disease/immunology/therapy

KW - Diet, Gluten-Free

KW - Duodenum/immunology

KW - Humans

KW - Inflammation/immunology

KW - Interleukin-6/metabolism

KW - Intestinal Mucosa/immunology

KW - Molecular Targeted Therapy

KW - RNA, Small Interfering/genetics

KW - Recurrence

KW - Signal Transduction

KW - Smad7 Protein/genetics/metabolism

KW - Transforming Growth Factor beta/metabolism

KW - Tumor Necrosis Factor-alpha/metabolism

KW - gluten

KW - inflammation

KW - mucosal immune response

KW - transforming growth factor-beta

U2 - 10.1111/imm.12690 [doi]

DO - 10.1111/imm.12690 [doi]

M3 - Article

VL - 150

SP - 356

EP - 363

JO - Immunology

JF - Immunology

SN - 0019-2805

IS - 3

ER -