PloS one, 2016-06, Vol.11 (6), p.e0157376-e0157376
2016
Details
- Autor(en) / Beteiligte
- Titel
- JAK-STAT6 Pathway Inhibitors Block Eotaxin-3 Secretion by Epithelial Cells and Fibroblasts from Esophageal Eosinophilia Patients: Promising Agents to Improve Inflammation and Prevent Fibrosis in EoE
- Ist Teil von
- PloS one, 2016-06, Vol.11 (6), p.e0157376-e0157376
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2016
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Although most studies on treatments for eosinophilic esophagitis (EoE) have focused on effects in the epithelium, EoE is a transmural disease. Eosinophils that infiltrate the subepithelial layers of the esophagus lead to fibrosis and the serious complications of EoE, and current therapies have shown minimal effects on this fibrosis. We aimed to elucidate T helper (Th)2 cytokine effects on esophageal fibroblasts and to explore potential fibroblast-targeted therapies for EoE. We established telomerase-immortalized fibroblasts from human esophageal biopsies. We stimulated these esophageal fibroblasts with Th2 cytokines, and examined effects of omeprazole and inhibitors of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT6) pathway (AS1517499, leflunomide, and ruxolitinib) on STAT6 phosphorylation, STAT6 nuclear translocation, and eotaxin-3 expression. We also measured the effects of these inhibitors in esophageal epithelial cells stimulated with Th2 cytokines. As in esophageal epithelial cells, Th2 cytokines increased STAT6 phosphorylation, STAT6 nuclear translocation, eotaxin-3 transcription and protein secretion in esophageal fibroblasts. Unlike in epithelial cells, however, omeprazole did not inhibit cytokine-stimulated eotaxin-3 expression in fibroblasts. In contrast, JAK-STAT6 pathway inhibitors decreased cytokine-stimulated eotaxin-3 expression in both fibroblasts and epithelial cells. Omeprazole does not inhibit Th2 cytokine-stimulated eotaxin-3 expression by esophageal fibroblasts, suggesting that PPIs will have limited impact on subepithelial EoE processes such as fibrosis. JAK-STAT6 pathway inhibitors block Th2 cytokine-stimulated eotaxin-3 expression both in fibroblasts and in epithelial cells, suggesting a potential role for JAK-STAT inhibitors in treating both epithelial inflammation and subepithelial fibrosis in EoE.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0157376Titel-ID: cdi_plos_journals_1797551403
- Format
- –
- Schlagworte
- Biology and Life Sciences, Blood diseases, Cancer therapies, Cell Line, Transformed, Chemokine CCL26, Chemokines, CC - antagonists & inhibitors, Chemokines, CC - genetics, Chemokines, CC - metabolism, Complications, Cytokines, Eosinophilia, Eosinophilic Esophagitis - drug therapy, Eosinophilic Esophagitis - genetics, Eosinophilic Esophagitis - metabolism, Eosinophilic Esophagitis - pathology, Eosinophils, Eosinophils - drug effects, Eosinophils - metabolism, Eosinophils - pathology, Eotaxin, Epithelial cells, Epithelial Cells - drug effects, Epithelial Cells - metabolism, Epithelial Cells - pathology, Epithelium, Esophageal diseases, Esophagitis, Esophagus, Fibroblasts, Fibroblasts - drug effects, Fibroblasts - metabolism, Fibroblasts - pathology, Fibrosis, Gene expression, Gene Expression Regulation, Humans, Inflammation, Inhibitors, Interleukin-13 - antagonists & inhibitors, Interleukin-13 - pharmacology, Interleukin-4 - antagonists & inhibitors, Interleukin-4 - pharmacology, Internal medicine, Isoxazoles - pharmacology, Janus kinase, Janus Kinase 1 - antagonists & inhibitors, Janus Kinase 1 - genetics, Janus Kinase 1 - metabolism, Leflunomide, Leukocytes (eosinophilic), Lymphocytes T, Medicine, Medicine and Health Sciences, Nuclear transport, Omeprazole, Omeprazole - pharmacology, Pathology, Pediatrics, Phosphorylation, Primary Cell Culture, Protein transport, Pyrazoles - pharmacology, Pyrimidines - pharmacology, Research and Analysis Methods, Rodents, Signal Transduction, Stat6 protein, STAT6 Transcription Factor - antagonists & inhibitors, STAT6 Transcription Factor - genetics, STAT6 Transcription Factor - metabolism, Telomerase, Th2 Cells - drug effects, Th2 Cells - metabolism, Th2 Cells - pathology, Transcription, Translocation, Veterans