title: Preferential Secretion of Thymic Stromal Lymphopoietin (TSLP) by Terminally Differentiated Esophageal Epithelial Cells: Relevance to Eosinophilic Esophagitis (EoE).
abstract: Eosinophilic esophagitis (EoE) is a chronic Th2 and food antigen-mediated disease characterized by esophageal eosinophilic infiltration. Thymic stromal lymphopoetin (TSLP), an epithelial derived cytokine which bridges innate and Th2-type adaptive immune responses in other allergic conditions, is overexpressed in esophageal biopsies of EoE subjects. However, the triggers of TSLP expression in the esophageal epithelium are unknown. The objective of the current study was to characterize TSLP expression in human esophageal epithelium in EoE in vivo and to determine the role of food antigens upon epithelial TSLP expression in vitro. Using immunohistochemistry (IHC), we localized TSLP in esophageal biopsies of active EoE (≥15 eos/hpf), inactive EoE (<15 eos/hpf) and non-EoE control subjects, and found that TSLP expression was restricted to the differentiated suprabasal layer of the epithelium in actively inflamed EoE biopsies. Consistent with these results in vivo, inducible TSLP protein secretion was higher in CaCl2 differentiated telomerase-immortalized esophageal epithelial cells (EPC2-hTERT) compared to undifferentiated cells of the basal phenotype, following stimulation with the TLR3 ligand poly(I:C). To determine whether food antigens could directly induce epithelial TSLP secretion, differentiated and undifferentiated primary esophageal epithelial cells from EoE and non-EoE subjects were challenged with food antigens clinically relevant to EoE: Chicken egg ovalbumin (OVA), wheat, and milk proteins beta-lactoglobulin (blg) and beta-casein. Food antigens failed to induce TSLP secretion by undifferentiated cells; in contrast, only OVA induced TSLP secretion in differentiated epithelial cells from both EoE and control cell lines, an effect abolished by budesonide and NF-κb inhibition. Together, our study shows that specific food antigens can trigger innate immune mediated esophageal TSLP secretion, suggesting that esophageal epithelial cells at the barrier surface may play a significant role in the pathogenesis of EoE by regulating TSLP expression.
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States of America.
authors.forename: Prasanna M
authors.initials: PM
authors.lastname: Chandramouleeswaran
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States of America.
authors.forename: Dawen
authors.initials: D
authors.lastname: Shen
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States of America.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Lee
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States of America.
authors.forename: Alain
authors.initials: A
authors.lastname: Benitez
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States of America.
authors.forename: Kara
authors.initials: K
authors.lastname: Dods
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States of America.
authors.forename: Fiona
authors.initials: F
authors.lastname: Gambanga
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States of America.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Wilkins
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States of America.|Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States of America.
authors.forename: Jamie
authors.initials: J
authors.lastname: Merves
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States of America.
authors.forename: Yuliana
authors.initials: Y
authors.lastname: Noah
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States of America.
authors.forename: Sarit
authors.initials: S
authors.lastname: Toltzis
authors.affiliation: Department of Immunology, Merck Research Labs, Palo Alto, California 94304, United States of America.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Yearley
authors.affiliation: Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States of America.|Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States of America.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Spergel
authors.affiliation: Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States of America.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Department of Immunology, Merck Research Labs, Palo Alto, California 94304, United States of America.
authors.forename: Rene deWaal
authors.initials: Rd
authors.lastname: Malefyt
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States of America.|Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States of America.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Muir
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States of America.|Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States of America.
authors.forename: Mei-Lun
authors.initials: ML
authors.lastname: Wang
mesh_terms: D000941:Antigens / Q000494:pharmacology; D019819:Budesonide / Q000494:pharmacology; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D057765:Eosinophilic Esophagitis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004947:Esophagus / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000941:Antigens; D016207:Cytokines; D016328:NF-kappa B; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D019819:Budesonide; D011070:Poly I-C; D000094632:Thymic Stromal Lymphopoietin