TGFβ1 single-nucleotide polymorphism C-509T alters mucosal cell function in pediatric eosinophilic esophagitis
Eosinophilic esophagitis (EoE) is a chronic Th2 antigen-driven disorder associated with tissue remodeling. Inflammation and remodeling lead to esophageal rigidity, strictures, and dysphagia. TGFβ1 drives esophageal remodeling including epithelial barrier dysfunction and subepithelial fibrosis. A fun...
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| Vydáno v: | Mucosal immunology Ročník 13; číslo 1; s. 110 - 117 |
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| Hlavní autoři: | , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
New York
Elsevier Inc
01.01.2020
Nature Publishing Group US Elsevier Limited |
| Témata: | |
| ISSN: | 1933-0219, 1935-3456, 1935-3456 |
| On-line přístup: | Získat plný text |
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| Shrnutí: | Eosinophilic esophagitis (EoE) is a chronic Th2 antigen-driven disorder associated with tissue remodeling. Inflammation and remodeling lead to esophageal rigidity, strictures, and dysphagia. TGFβ1 drives esophageal remodeling including epithelial barrier dysfunction and subepithelial fibrosis. A functional SNP in the TGFβ1 gene that increases its transcription (C-509T) is associated with elevated numbers of esophageal TGFβ1-expressing cells. We utilized esophageal biopsies and fibroblasts from TT-genotype EoE children to understand if TGFβ1 influenced fibroblast and epithelial cell function in vivo. Genotype TT EoE esophageal fibroblasts had higher baseline TGFβ1, collagen1α1, periostin, and MMP2 (p < 0.05) gene expression and distinct contractile properties compared with CC genotype (n = 6 subjects per genotype). In vitro TGFβ1 exposure caused greater induction of target gene expression in genotype CC fibroblasts (p < 0.05). Esophageal biopsies from TT-genotype subjects had significantly less epithelial membrane-bound E-cadherin (p < 0.01) and wider cluster distribution at nanometer resolution. TGFβ1 treatment of stratified primary human esophageal epithelial cells and spheroids disrupted transepithelial resistance (p < 0.001) and E-cadherin localization (p < 0.0001). A TGFβ1-receptor-I inhibitor improved TGFβ1-mediated E-cadherin mislocalization. These data suggest that EoE severity can depend on genotypic differences that increase in vivo exposure to TGFβ1. TGFβ1 inhibition may be a useful therapy in subsets of EoE patients. |
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| Bibliografie: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 MM: Designed, performed, and analyzed experiments and data, assisted in manuscript preparation, and critically reviewed the data. KB: Provided essential expertise, analyzed data, critically reviewed the manuscript RON: Analyzed data, provided essential expertise, critically reviewed the manuscript RD: Provided samples, assisted with experimental design, analyzed data, critically reviewed the manuscript RK: Provided samples, analyzed data, critically reviewed the manuscript LDD: Designed, performed, and analyzed experiments and data, assisted in manuscript preparation, and critically reviewed the manuscript RR: Designed, performed, and analyzed experiments and data, assisted in manuscript preparation, and critically reviewed the manuscript SSA: Designed experiments, procured funding, analyzed experimental data, wrote the manuscript AB: Designed, performed, and analyzed experiments and data, assisted in manuscript preparation, and critically reviewed the manuscript Author Contributions ZL: Provided essential expertise, analyzed data, critically reviewed the manuscript |
| ISSN: | 1933-0219 1935-3456 1935-3456 |
| DOI: | 10.1038/s41385-019-0214-9 |