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Identification of SMAD3 as a Novel Mediator of Inflammation in Human Myometrium In Vitro

Preterm birth remains the primary cause of early neonatal death and is a major determinant for long-term health consequences. Aberrant intrauterine inflammation and infection are known to augment the synthesis of proinflammatory cytokines and induce uterine contractions, which can subsequently lead...

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Autor principal: Lappas, Martha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180979/
https://www.ncbi.nlm.nih.gov/pubmed/30363688
http://dx.doi.org/10.1155/2018/3140420
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author Lappas, Martha
author_facet Lappas, Martha
author_sort Lappas, Martha
collection PubMed
description Preterm birth remains the primary cause of early neonatal death and is a major determinant for long-term health consequences. Aberrant intrauterine inflammation and infection are known to augment the synthesis of proinflammatory cytokines and induce uterine contractions, which can subsequently lead to preterm birth. The transforming growth factor-β (TGF-β) superfamily members regulate numerous cellular processes through the activation of intracellular mediators known as mothers against decapentaplegic homolog (SMADs). Studies in nongestational tissues have shown that SMAD3 plays a role in immune regulation and inflammation; however, its role in human labour remains unknown. Thus, the present study aimed at (i) characterising the expression of SMAD3 in the human myometrium; (ii) determining the effect of bacterial and viral products and proinflammatory cytokines on SMAD3 transcriptional activity in primary human myometrial cells; and (iii) investigating the effect of SMAD3 siRNA knockdown on the production of prolabour mediators in primary human myometrial cells. Phosphorylated (i.e., active) SMAD3 protein expression was lower in the myometrium after spontaneous term labour compared to the myometrium from nonlabouring women. Using a luciferase assay, the proinflammatory cytokines IL-1β and TNF, and viral analogue polyinosinic : polycytidylic acid (poly(I : C)) significantly reduced SMAD3 transcriptional activity in human primary myometrial cells. Loss-of-function studies found that SMAD3 knockdown in myometrial cells significantly increased IL-1β- and poly(I : C)-induced proinflammatory cytokines (IL-1A, IL-6), chemokines (IL-8, MCP-1), the adhesion molecule ICAM-1, COX-2 mRNA expression, and subsequent PGF(2α) release. In conclusion, SMAD3 deficiency is associated with increased production of proinflammatory and prolabour mediators in the human myometrium.
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spelling pubmed-61809792018-10-24 Identification of SMAD3 as a Novel Mediator of Inflammation in Human Myometrium In Vitro Lappas, Martha Mediators Inflamm Research Article Preterm birth remains the primary cause of early neonatal death and is a major determinant for long-term health consequences. Aberrant intrauterine inflammation and infection are known to augment the synthesis of proinflammatory cytokines and induce uterine contractions, which can subsequently lead to preterm birth. The transforming growth factor-β (TGF-β) superfamily members regulate numerous cellular processes through the activation of intracellular mediators known as mothers against decapentaplegic homolog (SMADs). Studies in nongestational tissues have shown that SMAD3 plays a role in immune regulation and inflammation; however, its role in human labour remains unknown. Thus, the present study aimed at (i) characterising the expression of SMAD3 in the human myometrium; (ii) determining the effect of bacterial and viral products and proinflammatory cytokines on SMAD3 transcriptional activity in primary human myometrial cells; and (iii) investigating the effect of SMAD3 siRNA knockdown on the production of prolabour mediators in primary human myometrial cells. Phosphorylated (i.e., active) SMAD3 protein expression was lower in the myometrium after spontaneous term labour compared to the myometrium from nonlabouring women. Using a luciferase assay, the proinflammatory cytokines IL-1β and TNF, and viral analogue polyinosinic : polycytidylic acid (poly(I : C)) significantly reduced SMAD3 transcriptional activity in human primary myometrial cells. Loss-of-function studies found that SMAD3 knockdown in myometrial cells significantly increased IL-1β- and poly(I : C)-induced proinflammatory cytokines (IL-1A, IL-6), chemokines (IL-8, MCP-1), the adhesion molecule ICAM-1, COX-2 mRNA expression, and subsequent PGF(2α) release. In conclusion, SMAD3 deficiency is associated with increased production of proinflammatory and prolabour mediators in the human myometrium. Hindawi 2018-09-27 /pmc/articles/PMC6180979/ /pubmed/30363688 http://dx.doi.org/10.1155/2018/3140420 Text en Copyright © 2018 Martha Lappas. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Lappas, Martha
Identification of SMAD3 as a Novel Mediator of Inflammation in Human Myometrium In Vitro
title Identification of SMAD3 as a Novel Mediator of Inflammation in Human Myometrium In Vitro
title_full Identification of SMAD3 as a Novel Mediator of Inflammation in Human Myometrium In Vitro
title_fullStr Identification of SMAD3 as a Novel Mediator of Inflammation in Human Myometrium In Vitro
title_full_unstemmed Identification of SMAD3 as a Novel Mediator of Inflammation in Human Myometrium In Vitro
title_short Identification of SMAD3 as a Novel Mediator of Inflammation in Human Myometrium In Vitro
title_sort identification of smad3 as a novel mediator of inflammation in human myometrium in vitro
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180979/
https://www.ncbi.nlm.nih.gov/pubmed/30363688
http://dx.doi.org/10.1155/2018/3140420
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