17β-Estradiol protects the esophageal epithelium from IL-13-induced barrier dysfunction and remodeling.
Adolescent
Adult
Cells, Cultured
Child
Child, Preschool
Eosinophilic Esophagitis
/ drug therapy
Esophagus
/ drug effects
Estradiol
/ therapeutic use
Female
Humans
Incidence
Interleukin-13
/ metabolism
Intestinal Mucosa
/ drug effects
Keratinocytes
/ physiology
Male
Primary Cell Culture
Receptors, Estrogen
/ metabolism
STAT6 Transcription Factor
/ metabolism
Sequence Analysis, RNA
Sex Factors
Signal Transduction
TYK2 Kinase
/ metabolism
Young Adult
Eosinophilic esophagitis
IL-13
barrier dysfunction
estrogen
hormone
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
12
07
2017
revised:
30
08
2018
accepted:
25
10
2018
pubmed:
24
12
2018
medline:
6
5
2020
entrez:
23
12
2018
Statut:
ppublish
Résumé
The incidence of eosinophilic esophagitis (EoE) is greater in male than female subjects, and the underlying molecular basis for this sex bias remains unclear. We sought to delineate the contribution of the sex hormone estrogen to the EoE phenotype and esophageal epithelial barrier function and remodeling. We performed demographic and incidence analyses of EoE in male and female subjects from a single-center pediatric cohort. Estrogen-responsive gene expression analyses and estrogen receptor (ESR) immunofluorescence staining of esophageal biopsy specimens from patients with EoE and control subjects were performed. The effect of 17β-estradiol (E2) on IL-13-induced signaling pathways, gene expression, and esophageal epithelial architecture and barrier function in a primary human esophageal keratinocyte cell (EPC2) culture system (EPC2-air-liquid interface) was examined. We observed a male predominance in patients with EoE. Analyses of RNA sequencing data sets revealed a significant dysregulation of the estrogen-responsive gene network and expression of ESR1 and ESR2 in esophageal biopsy specimens from patients with EoE compared with control subjects. IL-13 stimulation of EPC2-air-liquid interface cells led to altered cellular architecture with induced dilation of intercellular spaces and barrier dysfunction. Pretreatment of EPC2s with E2 prior to IL-13 exposure abrogated IL-13-induced architectural changes and esophageal barrier dysfunction. Mechanistically, E2-protective effects were dependent on ESR2 and associated with diminishing of IL-13-induced tyrosine kinase 2 and signal transducer and activator of transcription 6 phosphorylation and EoE-dysregulated gene expression. Estrogen-responsive genes are modified in patients with EoE compared with control subjects. E2 attenuated IL-13-induced architectural changes and esophageal epithelial barrier dysfunction through inhibition of the IL-13/tyrosine kinase 2/signal transducer and activator of transcription 6 pathway via ESR2-dependent process. Estrogen hormone signaling may protect against development of EoE in female subjects.
Sections du résumé
BACKGROUND
The incidence of eosinophilic esophagitis (EoE) is greater in male than female subjects, and the underlying molecular basis for this sex bias remains unclear.
OBJECTIVE
We sought to delineate the contribution of the sex hormone estrogen to the EoE phenotype and esophageal epithelial barrier function and remodeling.
METHODS
We performed demographic and incidence analyses of EoE in male and female subjects from a single-center pediatric cohort. Estrogen-responsive gene expression analyses and estrogen receptor (ESR) immunofluorescence staining of esophageal biopsy specimens from patients with EoE and control subjects were performed. The effect of 17β-estradiol (E2) on IL-13-induced signaling pathways, gene expression, and esophageal epithelial architecture and barrier function in a primary human esophageal keratinocyte cell (EPC2) culture system (EPC2-air-liquid interface) was examined.
RESULTS
We observed a male predominance in patients with EoE. Analyses of RNA sequencing data sets revealed a significant dysregulation of the estrogen-responsive gene network and expression of ESR1 and ESR2 in esophageal biopsy specimens from patients with EoE compared with control subjects. IL-13 stimulation of EPC2-air-liquid interface cells led to altered cellular architecture with induced dilation of intercellular spaces and barrier dysfunction. Pretreatment of EPC2s with E2 prior to IL-13 exposure abrogated IL-13-induced architectural changes and esophageal barrier dysfunction. Mechanistically, E2-protective effects were dependent on ESR2 and associated with diminishing of IL-13-induced tyrosine kinase 2 and signal transducer and activator of transcription 6 phosphorylation and EoE-dysregulated gene expression.
CONCLUSIONS
Estrogen-responsive genes are modified in patients with EoE compared with control subjects. E2 attenuated IL-13-induced architectural changes and esophageal epithelial barrier dysfunction through inhibition of the IL-13/tyrosine kinase 2/signal transducer and activator of transcription 6 pathway via ESR2-dependent process. Estrogen hormone signaling may protect against development of EoE in female subjects.
Identifiants
pubmed: 30578870
pii: S0091-6749(18)32778-7
doi: 10.1016/j.jaci.2018.10.070
pmc: PMC6556402
mid: NIHMS1015718
pii:
doi:
Substances chimiques
Interleukin-13
0
Receptors, Estrogen
0
STAT6 Transcription Factor
0
Estradiol
4TI98Z838E
TYK2 Kinase
EC 2.7.10.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2131-2146Subventions
Organisme : NIDDK NIH HHS
ID : T32 DK007727
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI140133
Pays : United States
Organisme : NIAMS NIH HHS
ID : P30 AR070549
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK064008
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007413
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI112626
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK078392
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI112626
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK090119
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001425
Pays : United States
Informations de copyright
Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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