Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic InflammationSummary

Background & Aims: Aberrant immune activation is associated with numerous inflammatory and autoimmune diseases and contributes to cancer development and progression. Within the stomach, inflammation drives a well-established sequence from gastritis to metaplasia, eventually resulting in aden...

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Autores principales:	Jonathan T. Busada, Stuti Khadka, Kylie N. Peterson, Sara R. Druffner, Deborah J. Stumpo, Lecong Zhou, Robert H. Oakley, John A. Cidlowski, Perry J. Blackshear
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	gastric inflammation, adrenalectomy, SPEM, gastric cancer Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/876709e33caf46139fe9a9eaa46c5efb
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spelling	oai:doaj.org-article:876709e33caf46139fe9a9eaa46c5efb2021-11-12T04:39:20ZTristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic InflammationSummary2352-345X10.1016/j.jcmgh.2021.07.015https://doaj.org/article/876709e33caf46139fe9a9eaa46c5efb2021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001612https://doaj.org/toc/2352-345XBackground & Aims: Aberrant immune activation is associated with numerous inflammatory and autoimmune diseases and contributes to cancer development and progression. Within the stomach, inflammation drives a well-established sequence from gastritis to metaplasia, eventually resulting in adenocarcinoma. Unfortunately, the processes that regulate gastric inflammation and prevent carcinogenesis remain unknown. Tristetraprolin (TTP) is an RNA-binding protein that promotes the turnover of numerous proinflammatory and oncogenic messenger RNAs. Here, we assess the role of TTP in regulating gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM) development. Methods: We used a TTP-overexpressing model, the TTPΔadenylate-uridylate rich element mouse, to examine whether TTP can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and SPEM. Results: We found that TTPΔadenylate-uridylate rich element mice were completely protected from ADX-induced gastric inflammation and SPEM. RNA sequencing 5 days after ADX showed that TTP overexpression suppressed the expression of genes associated with the innate immune response. Importantly, TTP overexpression did not protect from high-dose-tamoxifen–induced SPEM development, suggesting that protection in the ADX model is achieved primarily by suppressing inflammation. Finally, we show that protection from gastric inflammation was only partially due to the suppression of Tnf, a well-known TTP target. Conclusions: Our results show that TTP exerts broad anti-inflammatory effects in the stomach and suggest that therapies that increase TTP expression may be effective treatments of proneoplastic gastric inflammation. Transcript profiling: GSE164349.Jonathan T. BusadaStuti KhadkaKylie N. PetersonSara R. DruffnerDeborah J. StumpoLecong ZhouRobert H. OakleyJohn A. CidlowskiPerry J. BlackshearElsevierarticlegastric inflammation, adrenalectomy, SPEM, gastric cancerDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 5, Pp 1831-1845 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	gastric inflammation, adrenalectomy, SPEM, gastric cancer Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	gastric inflammation, adrenalectomy, SPEM, gastric cancer Diseases of the digestive system. Gastroenterology RC799-869 Jonathan T. Busada Stuti Khadka Kylie N. Peterson Sara R. Druffner Deborah J. Stumpo Lecong Zhou Robert H. Oakley John A. Cidlowski Perry J. Blackshear Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic InflammationSummary
description	Background & Aims: Aberrant immune activation is associated with numerous inflammatory and autoimmune diseases and contributes to cancer development and progression. Within the stomach, inflammation drives a well-established sequence from gastritis to metaplasia, eventually resulting in adenocarcinoma. Unfortunately, the processes that regulate gastric inflammation and prevent carcinogenesis remain unknown. Tristetraprolin (TTP) is an RNA-binding protein that promotes the turnover of numerous proinflammatory and oncogenic messenger RNAs. Here, we assess the role of TTP in regulating gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM) development. Methods: We used a TTP-overexpressing model, the TTPΔadenylate-uridylate rich element mouse, to examine whether TTP can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and SPEM. Results: We found that TTPΔadenylate-uridylate rich element mice were completely protected from ADX-induced gastric inflammation and SPEM. RNA sequencing 5 days after ADX showed that TTP overexpression suppressed the expression of genes associated with the innate immune response. Importantly, TTP overexpression did not protect from high-dose-tamoxifen–induced SPEM development, suggesting that protection in the ADX model is achieved primarily by suppressing inflammation. Finally, we show that protection from gastric inflammation was only partially due to the suppression of Tnf, a well-known TTP target. Conclusions: Our results show that TTP exerts broad anti-inflammatory effects in the stomach and suggest that therapies that increase TTP expression may be effective treatments of proneoplastic gastric inflammation. Transcript profiling: GSE164349.
format	article
author	Jonathan T. Busada Stuti Khadka Kylie N. Peterson Sara R. Druffner Deborah J. Stumpo Lecong Zhou Robert H. Oakley John A. Cidlowski Perry J. Blackshear
author_facet	Jonathan T. Busada Stuti Khadka Kylie N. Peterson Sara R. Druffner Deborah J. Stumpo Lecong Zhou Robert H. Oakley John A. Cidlowski Perry J. Blackshear
author_sort	Jonathan T. Busada
title	Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic InflammationSummary
title_short	Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic InflammationSummary
title_full	Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic InflammationSummary
title_fullStr	Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic InflammationSummary
title_full_unstemmed	Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic InflammationSummary
title_sort	tristetraprolin prevents gastric metaplasia in mice by suppressing pathogenic inflammationsummary
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/876709e33caf46139fe9a9eaa46c5efb
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_version_	1718431240588099584

Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic InflammationSummary

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