17?-Estradiol protects the esophageal epithelium from IL-13–induced barrier dysfunction and remodeling - 06/06/19
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Eosinophilic esophagitis, IL-13, estrogen, hormone, barrier dysfunction
Abbreviations used : AD, ALI, CCED, DIS, DSG1, E2, EDP, EoE, EPC2, ESR, FC, IL-4R, IL-13Rα, JAK, MPP, NF, PHTPP, pSTAT6, pTYK2, RNA-seq, RPKM, SOCS, STAT6, TER, TYK2
Plan
| Supported by Food Allergy Research & Education, the National Institutes of Health (grant nos. AI112626 and DK090119 to S.P.H., T32 DK007727 to J.C.W., and P30 DK078392), the Campaign Urging Research for Eosinophilic Disease (CURED) Foundation; and the Sunshine Charitable Foundation and its supporters, Denise A. Bunning and David G. Bunning and the Mary H Weiser Food Allergy Center. |
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| Disclosure of potential conflict of interest: V. Mukkada is a consultant and receives research funding from Shire. M. E. Rothenberg is a consultant for PulmOne, Spoon Guru, ClostraBio, Celgene, Shire, AstraZeneca, GlaxoSmithKline, Allakos, Adare, Regeneron, and Novartis and has an equity interest in the first 4 listed and Immune Pharmaceuticals and receives royalties from reslizumab (Teva Pharmaceuticals) and UpToDate; he is also an inventor of patents owned by Cincinnati Children's Hospital Medical Center. S. P. Hogan is an inventor of patents owned by Cincinnati Children's Hospital Medical Center. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 143 - N° 6
P. 2131-2146 - juin 2019 Retour au numéro
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