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.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Esophageal Diseases Center, Veterans Affairs North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Department of Pediatrics, Children's Health Children's Medical Center, Dallas, Texas, United States of America.|Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Medical Services, Veterans Affairs North Texas Health Care System, Dallas, Texas, United States of America.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Edaire
E
Cheng
Esophageal Diseases Center, Veterans Affairs North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Medical Services, Veterans Affairs North Texas Health Care System, Dallas, Texas, United States of America.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Xi
X
Zhang
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Kathleen S
KS
Wilson
Esophageal Diseases Center, Veterans Affairs North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Medical Services, Veterans Affairs North Texas Health Care System, Dallas, Texas, United States of America.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
David H
DH
Wang
Esophageal Diseases Center, Veterans Affairs North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Department of Pathology, Children's Health Children's Medical Center, Dallas, Texas, United States of America.
Jason Y
JY
Park
Esophageal Diseases Center, Veterans Affairs North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Medical Services, Veterans Affairs North Texas Health Care System, Dallas, Texas, United States of America.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Xiaofang
X
Huo
Esophageal Diseases Center, Veterans Affairs North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Medical Services, Veterans Affairs North Texas Health Care System, Dallas, Texas, United States of America.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Chunhua
C
Yu
Esophageal Diseases Center, Veterans Affairs North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Medical Services, Veterans Affairs North Texas Health Care System, Dallas, Texas, United States of America.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Qiuyang
Q
Zhang
Esophageal Diseases Center, Veterans Affairs North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Medical Services, Veterans Affairs North Texas Health Care System, Dallas, Texas, United States of America.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Stuart J
SJ
Spechler
Esophageal Diseases Center, Veterans Affairs North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Medical Services, Veterans Affairs North Texas Health Care System, Dallas, Texas, United States of America.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Rhonda F
RF
Souza
D002461:Cell Line, Transformed; D000075906:Chemokine CCL26; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057765:Eosinophilic Esophagitis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology*; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077339:Leflunomide; D009570:Nitriles; D009853:Omeprazole / Q000494:pharmacology; D010766:Phosphorylation; D061251:Primary Cell Culture; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
C544923:4-(benzylamino)-2-((2-(3-chloro-4-hydroxyphenyl)ethyl)amino)pyrimidine-5-carboxamide; C120429:CCL26 protein, human; D000075906:Chemokine CCL26; D019742:Chemokines, CC; C578095:IL13 protein, human; C508598:IL4 protein, human; D018793:Interleukin-13; D007555:Isoxazoles; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4; C540383:ruxolitinib; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D000077339:Leflunomide; D009853:Omeprazole