Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic Inflammation.
Animals
Biomarkers
Disease Models, Animal
Disease Susceptibility
Fluorescent Antibody Technique
Gastric Mucosa
/ metabolism
Gene Expression Regulation
Immunohistochemistry
Inflammation
/ complications
Metaplasia
/ etiology
Mice
Mice, Knockout
Tamoxifen
/ administration & dosage
Tristetraprolin
/ genetics
gastric inflammation, adrenalectomy, SPEM, gastric cancer
Journal
Cellular and molecular gastroenterology and hepatology
ISSN: 2352-345X
Titre abrégé: Cell Mol Gastroenterol Hepatol
Pays: United States
ID NLM: 101648302
Informations de publication
Date de publication:
2021
2021
Historique:
received:
25
01
2021
revised:
27
07
2021
accepted:
27
07
2021
pubmed:
7
8
2021
medline:
29
3
2022
entrez:
6
8
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 34358715
pii: S2352-345X(21)00161-2
doi: 10.1016/j.jcmgh.2021.07.015
pmc: PMC8554534
pii:
doi:
Substances chimiques
Biomarkers
0
Tristetraprolin
0
Tamoxifen
094ZI81Y45
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1831-1845Subventions
Organisme : NCRR NIH HHS
ID : P20 RR016440
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA ES090080
Pays : United States
Organisme : NIGMS NIH HHS
ID : FI2 GM123974
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM103503
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM121322
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103434
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM103488
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM104942
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA ES090057
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.