Broad transcriptional response of the human esophageal epithelium to proton pump inhibitors - 05/05/21
Abstract |
Background |
Proton pump inhibitors (PPIs) have been recognized as a primary treatment of eosinophilic esophagitis (EoE), an allergic inflammatory disease of the esophageal mucosa. The mechanisms underlying esophageal epithelial responses to PPIs remain poorly understood.
Objective |
We hypothesized that PPIs can counteract IL-13–mediated esophageal epithelial responses that are germane for EoE pathogenesis.
Methods |
Transcriptional responses of human esophageal cells to IL-13 and the PPIs omeprazole and esomeprazole were assessed by RT-PCR and RNA sequencing. Cytokine secretion was measured by multiplex analysis and ELISA.
Results |
Human esophageal epithelial cells robustly responded to PPI stimulation by inducing a set of 479 core genes common between omeprazole and esomeprazole treatments. The transcriptional response to PPIs was partially mediated through the aryl hydrocarbon receptor signaling pathway, as the aryl hydrocarbon receptor antagonist GNF-351 modified approximately 200 genes, particularly those enriched in metabolic processes and regulation of cell death. PPI treatment reversed approximately 20% of the IL-13 transcriptome. Functional analysis of the PPI-responsive, upregulated genes revealed enrichment in metabolic and oxidation processes, and the unfolded protein response. In contrast, downregulated genes were overrepresented in functional terms related to cell division and cytoskeletal organization, which were also enriched for the genes in the EoE transcriptome reversed by PPIs. Furthermore, PPI treatment decreased the IL-13–induced proliferative response of esophageal epithelial cells.
Conclusions |
These results demonstrate broad effects of PPIs on esophageal epithelium, including their ability to curtail transcriptomic processes involved in cellular proliferation and IL-13–induced responses, and they highlight the importance of AHR signaling in mediating these responses.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Proton pump inhibitors, omeprazole, esomeprazole, eosinophilic esophagitis, epithelium, IL-13, aryl hydrocarbon receptor
Abbreviations used : AHR, ALI, ATPase, CCHMC, EoE, GO, KSFM, PPI, STAT6, TEER
Plan
Supported by the National Institutes of Health (grants R37 AI045898, R01 AI124355, U19 AI070235, and P30 DK078392 [Gene and Protein Expression Core]); the Campaign Urging Research for Eosinophilic Disease (CURED) (M.E.R.); the Buckeye Foundation (M.E.R.); the Sunshine Charitable Foundation and its supporters Denise A. Bunning and David G. Bunning (M.E.R.); and the Key Research and Development Project of Sichuan Provincial Science and Technology Program, China (grant 2019YFG0165, Y.-M. X.). |
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Disclosure of potential conflict of interest: M. E. Rothenberg is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celgene, AstraZeneca, Arena Pharmaceuticals, Guidepoint, and Suvretta Capital Management and has an equity interest in the first 5 of the aforementioned companies and receives royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate. In addition, M. E. Rothenberg is an inventor of patents owned by Cincinnati Children’s Hospital. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 147 - N° 5
P. 1924-1935 - mai 2021 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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