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High SMAD7 and p-SMAD2,3 expression is associated with environmental enteropathy in children

Enteropathies such as Crohn’s disease are associated with enteric inflammation characterized by impaired TGF-β signaling, decreased expression of phosphorylated (p)-SMAD2,3 and increased expression of SMAD7 (an inhibitor of SMAD3 phosphorylation). Environmental enteropathy (EE) is an acquired inflam...

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Autores principales: Syed, Sana, Dinallo, Vincenzo, Iqbal, Najeeha T., Di Iorio, Laura, Di Fusco, Davide, Guleria, Shan, Amadi, Beatrice C., Sadiq, Kamran, Moskaluk, Christopher, Ali, S. Asad, Kelly, Paul, Monteleone, Giovanni
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819826/
https://www.ncbi.nlm.nih.gov/pubmed/29415065
http://dx.doi.org/10.1371/journal.pntd.0006224
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author Syed, Sana
Dinallo, Vincenzo
Iqbal, Najeeha T.
Di Iorio, Laura
Di Fusco, Davide
Guleria, Shan
Amadi, Beatrice C.
Sadiq, Kamran
Moskaluk, Christopher
Ali, S. Asad
Kelly, Paul
Monteleone, Giovanni
author_facet Syed, Sana
Dinallo, Vincenzo
Iqbal, Najeeha T.
Di Iorio, Laura
Di Fusco, Davide
Guleria, Shan
Amadi, Beatrice C.
Sadiq, Kamran
Moskaluk, Christopher
Ali, S. Asad
Kelly, Paul
Monteleone, Giovanni
author_sort Syed, Sana
collection PubMed
description Enteropathies such as Crohn’s disease are associated with enteric inflammation characterized by impaired TGF-β signaling, decreased expression of phosphorylated (p)-SMAD2,3 and increased expression of SMAD7 (an inhibitor of SMAD3 phosphorylation). Environmental enteropathy (EE) is an acquired inflammatory disease of the small intestine (SI), which is associated with linear growth disruption, cognitive deficits, and reduced oral vaccine responsiveness in children <5 y in resource-poor countries. We aimed to characterize EE inflammatory pathways by determining SMAD7 and p-SMAD2,3 levels (using Western blotting) in EE duodenal biopsies (N = 19 children, 7 from Pakistan, 12 from Zambia) and comparing these with healthy controls (Ctl) and celiac disease (CD) patients from Italy. Densitometric analysis of immunoblots showed that EE SI biopsies expressed higher levels of both SMAD7 (mean±SD in arbitrary units [a.u.], Ctl = 0.47±0.20 a.u., EE = 1.13±0.25 a.u., p-value = 0.03) and p-SMAD2,3 (mean±SD, Ctl = 0.38±0.14 a.u., EE = 0.60±0.10 a.u., p-value = 0.03). Immunohistochemistry showed that, in EE, SMAD7 is expressed in both the epithelium and in mononuclear cells of the lamina propria (LP). In contrast, p-SMAD3 in EE is expressed much more prominently in epithelial cells than in the LP. The high SMAD7 immunoreactivity and lack of p-SMAD3 expression in the LP suggests defective TGF-β signaling in the LP in EE similar to a previously reported SMAD7-mediated inflammatory pathway in refractory CD and Crohn’s disease. However, Western blot densitometry showed elevated p-SMAD2,3 levels in EE, possibly suggesting a different inflammatory pathway than Crohn’s disease but more likely reflecting cumulative protein expression from across all compartments of the mucosa as opposed to the LP alone. Further studies are needed to substantiate these preliminary results and to illustrate the relationship between SMAD proteins, TGF-β signaling, and inflammatory cytokine production, all of which may be potential therapeutic targets.
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spelling pubmed-58198262018-03-15 High SMAD7 and p-SMAD2,3 expression is associated with environmental enteropathy in children Syed, Sana Dinallo, Vincenzo Iqbal, Najeeha T. Di Iorio, Laura Di Fusco, Davide Guleria, Shan Amadi, Beatrice C. Sadiq, Kamran Moskaluk, Christopher Ali, S. Asad Kelly, Paul Monteleone, Giovanni PLoS Negl Trop Dis Research Article Enteropathies such as Crohn’s disease are associated with enteric inflammation characterized by impaired TGF-β signaling, decreased expression of phosphorylated (p)-SMAD2,3 and increased expression of SMAD7 (an inhibitor of SMAD3 phosphorylation). Environmental enteropathy (EE) is an acquired inflammatory disease of the small intestine (SI), which is associated with linear growth disruption, cognitive deficits, and reduced oral vaccine responsiveness in children <5 y in resource-poor countries. We aimed to characterize EE inflammatory pathways by determining SMAD7 and p-SMAD2,3 levels (using Western blotting) in EE duodenal biopsies (N = 19 children, 7 from Pakistan, 12 from Zambia) and comparing these with healthy controls (Ctl) and celiac disease (CD) patients from Italy. Densitometric analysis of immunoblots showed that EE SI biopsies expressed higher levels of both SMAD7 (mean±SD in arbitrary units [a.u.], Ctl = 0.47±0.20 a.u., EE = 1.13±0.25 a.u., p-value = 0.03) and p-SMAD2,3 (mean±SD, Ctl = 0.38±0.14 a.u., EE = 0.60±0.10 a.u., p-value = 0.03). Immunohistochemistry showed that, in EE, SMAD7 is expressed in both the epithelium and in mononuclear cells of the lamina propria (LP). In contrast, p-SMAD3 in EE is expressed much more prominently in epithelial cells than in the LP. The high SMAD7 immunoreactivity and lack of p-SMAD3 expression in the LP suggests defective TGF-β signaling in the LP in EE similar to a previously reported SMAD7-mediated inflammatory pathway in refractory CD and Crohn’s disease. However, Western blot densitometry showed elevated p-SMAD2,3 levels in EE, possibly suggesting a different inflammatory pathway than Crohn’s disease but more likely reflecting cumulative protein expression from across all compartments of the mucosa as opposed to the LP alone. Further studies are needed to substantiate these preliminary results and to illustrate the relationship between SMAD proteins, TGF-β signaling, and inflammatory cytokine production, all of which may be potential therapeutic targets. Public Library of Science 2018-02-07 /pmc/articles/PMC5819826/ /pubmed/29415065 http://dx.doi.org/10.1371/journal.pntd.0006224 Text en © 2018 Syed et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Syed, Sana
Dinallo, Vincenzo
Iqbal, Najeeha T.
Di Iorio, Laura
Di Fusco, Davide
Guleria, Shan
Amadi, Beatrice C.
Sadiq, Kamran
Moskaluk, Christopher
Ali, S. Asad
Kelly, Paul
Monteleone, Giovanni
High SMAD7 and p-SMAD2,3 expression is associated with environmental enteropathy in children
title High SMAD7 and p-SMAD2,3 expression is associated with environmental enteropathy in children
title_full High SMAD7 and p-SMAD2,3 expression is associated with environmental enteropathy in children
title_fullStr High SMAD7 and p-SMAD2,3 expression is associated with environmental enteropathy in children
title_full_unstemmed High SMAD7 and p-SMAD2,3 expression is associated with environmental enteropathy in children
title_short High SMAD7 and p-SMAD2,3 expression is associated with environmental enteropathy in children
title_sort high smad7 and p-smad2,3 expression is associated with environmental enteropathy in children
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819826/
https://www.ncbi.nlm.nih.gov/pubmed/29415065
http://dx.doi.org/10.1371/journal.pntd.0006224
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