Broad transcriptional response of the human esophageal epithelium to proton pump inhibitors

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:147

Article

Rochman, Mark¹  Xie, Yong Mei^1,3,4  Mack, Lydia¹  Caldwell, Julie M.¹  Klingler, Andrea M.¹  Osswald, Garrett A.¹  Azouz, Nurit P.^1,2  Rothenberg, Marc E.^1,2 

[1] Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, 3333 Burnet Ave,MLC 7028, Cincinnati, OH 45229 USA

[2] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA

[3] Sichuan Univ, West China Univ Hosp 2, Dept Pediat, Chengdu, Sichuan, Peoples R China

[4] Sichuan Univ, Minist Educ, Key Lab Birth Defects & Related Dis Women & Child, Chengdu, Sichuan, Peoples R China

关键词: Proton pump inhibitors;    omeprazole;    esomeprazole;    eosinophilic esophagitis;    epithelium;    IL-13;    aryl hydrocarbon receptor;   

DOI  :  10.1016/j.jaci.2020.09.039

来源: Elsevier

【 摘 要 】

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. (J Allergy Clin Immunol 2021;147:1924-35.)

【 授权许可】

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