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FOXO1 inhibits FSL-1 regulation of integrin β6 by blocking STAT3 binding to the integrin β6 gene promoter

Integrin β6 (ITGB6), an epithelial-specific receptor, is downregulated in the gingival epithelium of periodontitis and is associated with inflammation response and periodontitis development. However, the transcriptional regulatory mechanism of ITGB6 downregulation in the human gingival epithelium re...

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Autores principales: Xu, Mingyan, Huang, Jie, Zhu, Feixiang, Shen, Kailun, Liu, Fan, Deng, Xiaoling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9589051/
https://www.ncbi.nlm.nih.gov/pubmed/36299623
http://dx.doi.org/10.3389/fcimb.2022.998693
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author Xu, Mingyan
Huang, Jie
Zhu, Feixiang
Shen, Kailun
Liu, Fan
Deng, Xiaoling
author_facet Xu, Mingyan
Huang, Jie
Zhu, Feixiang
Shen, Kailun
Liu, Fan
Deng, Xiaoling
author_sort Xu, Mingyan
collection PubMed
description Integrin β6 (ITGB6), an epithelial-specific receptor, is downregulated in the gingival epithelium of periodontitis and is associated with inflammation response and periodontitis development. However, the transcriptional regulatory mechanism of ITGB6 downregulation in the human gingival epithelium remains unclear. Fibroblast-stimulating lipopeptide-1 (FSL-1), an oral biofilm component, promotes an epithelial cell-driven proinflammatory response in periodontitis partially by suppressing ITGB6 expression. The aim of the current study was to investigate the transcriptional regulatory mechanism of ITGB6 inhibition by FSL-1 in human epithelial cells (HaCaT and primary human gingival epithelial cells), and to delineate the transcriptional mechanism of ITGB6 suppression in periodontitis. We found that FSL-1 inhibited ITGB6 transcription through increasing forkhead box protein O1 (FOXO1) expression and inhibiting signal transducer and activator of transcription 3 (STAT3) activation. Furthermore, FOXO1 bound to STAT3 directly, leading to decreased STAT3 phosphorylation induced by FSL-1. Consequently, the binding of phosphorylated STAT3 to the ITGB6 promoter was decreased, and ITGB6 transcription was therefore downregulated following FSL-1 stimulation. The reciprocal action of STAT3 and FOXO1 on ITGB6 downregulation was also confirmed by the immunostaining of the inflammatory epithelium associated with periodontitis. Our findings suggest that the interaction of FOXO1–STAT3 may be a useful signal target for the treatment of periodontitis.
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spelling pubmed-95890512022-10-25 FOXO1 inhibits FSL-1 regulation of integrin β6 by blocking STAT3 binding to the integrin β6 gene promoter Xu, Mingyan Huang, Jie Zhu, Feixiang Shen, Kailun Liu, Fan Deng, Xiaoling Front Cell Infect Microbiol Cellular and Infection Microbiology Integrin β6 (ITGB6), an epithelial-specific receptor, is downregulated in the gingival epithelium of periodontitis and is associated with inflammation response and periodontitis development. However, the transcriptional regulatory mechanism of ITGB6 downregulation in the human gingival epithelium remains unclear. Fibroblast-stimulating lipopeptide-1 (FSL-1), an oral biofilm component, promotes an epithelial cell-driven proinflammatory response in periodontitis partially by suppressing ITGB6 expression. The aim of the current study was to investigate the transcriptional regulatory mechanism of ITGB6 inhibition by FSL-1 in human epithelial cells (HaCaT and primary human gingival epithelial cells), and to delineate the transcriptional mechanism of ITGB6 suppression in periodontitis. We found that FSL-1 inhibited ITGB6 transcription through increasing forkhead box protein O1 (FOXO1) expression and inhibiting signal transducer and activator of transcription 3 (STAT3) activation. Furthermore, FOXO1 bound to STAT3 directly, leading to decreased STAT3 phosphorylation induced by FSL-1. Consequently, the binding of phosphorylated STAT3 to the ITGB6 promoter was decreased, and ITGB6 transcription was therefore downregulated following FSL-1 stimulation. The reciprocal action of STAT3 and FOXO1 on ITGB6 downregulation was also confirmed by the immunostaining of the inflammatory epithelium associated with periodontitis. Our findings suggest that the interaction of FOXO1–STAT3 may be a useful signal target for the treatment of periodontitis. Frontiers Media S.A. 2022-10-10 /pmc/articles/PMC9589051/ /pubmed/36299623 http://dx.doi.org/10.3389/fcimb.2022.998693 Text en Copyright © 2022 Xu, Huang, Zhu, Shen, Liu and Deng https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular and Infection Microbiology
Xu, Mingyan
Huang, Jie
Zhu, Feixiang
Shen, Kailun
Liu, Fan
Deng, Xiaoling
FOXO1 inhibits FSL-1 regulation of integrin β6 by blocking STAT3 binding to the integrin β6 gene promoter
title FOXO1 inhibits FSL-1 regulation of integrin β6 by blocking STAT3 binding to the integrin β6 gene promoter
title_full FOXO1 inhibits FSL-1 regulation of integrin β6 by blocking STAT3 binding to the integrin β6 gene promoter
title_fullStr FOXO1 inhibits FSL-1 regulation of integrin β6 by blocking STAT3 binding to the integrin β6 gene promoter
title_full_unstemmed FOXO1 inhibits FSL-1 regulation of integrin β6 by blocking STAT3 binding to the integrin β6 gene promoter
title_short FOXO1 inhibits FSL-1 regulation of integrin β6 by blocking STAT3 binding to the integrin β6 gene promoter
title_sort foxo1 inhibits fsl-1 regulation of integrin β6 by blocking stat3 binding to the integrin β6 gene promoter
topic Cellular and Infection Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9589051/
https://www.ncbi.nlm.nih.gov/pubmed/36299623
http://dx.doi.org/10.3389/fcimb.2022.998693
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