Details
- Autor(en) / Beteiligte
- Titel
- Omeprazole blocks STAT6 binding to the eotaxin-3 promoter in eosinophilic esophagitis cells
- Ist Teil von
- PloS one, 2012-11, Vol.7 (11), p.e50037
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Patients who have esophageal eosinophilia without gastroesophageal reflux disease (GERD) nevertheless can respond to proton pump inhibitors (PPIs), which can have anti-inflammatory actions independent of effects on gastric acid secretion. In esophageal cell cultures, omeprazole has been reported to inhibit Th2 cytokine-stimulated expression of eotaxin-3, an eosinophil chemoattractant contributing to esophageal eosinophilia in eosinophilic esophagitis (EoE). The objective of this study was to elucidate molecular mechanisms underlying PPI inhibition of IL-4-stimulated eotaxin-3 production by esophageal cells. Telomerase-immortalized and primary cultures of esophageal squamous cells from EoE patients were treated with IL-4 in the presence or absence of acid-activated omeprazole or lansoprazole. We measured eotaxin-3 protein secretion by ELISA, mRNA expression by PCR, STAT6 phosphorylation and nuclear translocation by Western blotting, eotaxin-3 promoter activation by an exogenous reporter construct, and STAT6, RNA polymerase II, and trimethylated H3K4 binding to the endogenous eotaxin-3 promoter by ChIP assay. Omeprazole in concentrations ≥5 µM significantly decreased IL-4-stimulated eotaxin-3 protein secretion and mRNA expression. Lansoprazole also blocked eotaxin-3 protein secretion. Omeprazole had no effect on eotaxin-3 mRNA stability or on STAT6 phosphorylation and STAT6 nuclear translocation. Rather, omeprazole blocked binding of IL-4-stimulated STAT6, RNA polymerase II, and trimethylated H3K4 to the eotaxin-3 promoter. PPIs, in concentrations achieved in blood with conventional dosing, significantly inhibit IL-4-stimulated eotaxin-3 expression in EoE esophageal cells and block STAT6 binding to the promoter. These findings elucidate molecular mechanisms whereby patients with Th2 cytokine-driven esophageal eosinophilia can respond to PPIs, independent of effects on gastric acid secretion.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0050037Titel-ID: cdi_plos_journals_1326644773
- Format
- –
- Schlagworte
- Acidification, Acids, Asthma, Autoimmune diseases, Binding, Biology, Biopsy, Blood diseases, Cancer, Care and treatment, Cell Culture Techniques, Chemokine CCL26, Chemokines, CC - biosynthesis, Chemokines, CC - genetics, Chemokines, CC - metabolism, Cytokines, Disease, DNA-Binding Proteins - drug effects, DNA-directed RNA polymerase, Dysphagia, Enzyme-linked immunosorbent assay, Eosinophilia, Eosinophilic Esophagitis - drug therapy, Eosinophilic Esophagitis - metabolism, Eosinophilic Esophagitis - pathology, Eosinophils - cytology, Eosinophils - drug effects, Eosinophils - metabolism, Eotaxin, Esophageal diseases, Esophagitis, Esophagus, Gastric Acid - metabolism, Gastroesophageal reflux, Gastrointestinal diseases, Gene expression, Gene Expression Regulation - drug effects, Humans, Inflammation, Interleukin 4, Interleukin-4 - administration & dosage, Interleukin-4 - metabolism, Internal medicine, Lansoprazole, Leukocytes (eosinophilic), Lymphocytes T, Medicine, Messenger RNA, Molecular modelling, mRNA stability, Nuclear transport, Omeprazole, Omeprazole - administration & dosage, Patients, Phosphorylation, Production methods, Promoter Regions, Genetic - drug effects, Proton pump inhibitors, Proton Pump Inhibitors - administration & dosage, Ribonucleic acid, RNA, RNA polymerase, RNA polymerase II, RNA Polymerase II - metabolism, Squamous cells, Stat6 protein, STAT6 Transcription Factor - genetics, STAT6 Transcription Factor - metabolism, Telomerase, Translocation, Ulcers, Veterans, Western blotting