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Interleukin 9 Alters Epithelial Barrier and E-cadherin in Eosinophilic Esophagitis

Doshi, Ashmi*,‡,§; Khamishon, Rebecca*,‡,§; Rawson, Renee*,‡; Duong, Loan*,‡; Dohil, Lucas*,‡; Myers, Stephen J.*,‡,§; Bell, Braxton*,‡; Dohil, Ranjan†,‡; Newbury, Robert O.‡,||; Barrett, Kim E.*,†,§; Kurten, Richard C.; Aceves, Seema S.*,‡,§

Journal of Pediatric Gastroenterology and Nutrition: February 2019 - Volume 68 - Issue 2 - p 225–231
doi: 10.1097/MPG.0000000000002144
Original Articles: Gastroenterology: Eosinophilic GI Disease

Background: Eosinophilic esophagitis (EoE) is a chronic TH2-assocated inflammatory condition accompanied by substantial impairments in epithelial barrier function and increased numbers of interleukin 9 (IL-9) expressing inflammatory cells. While IL-9 is known to affect barrier function in the intestine, the functional effects of IL-9 on the esophagus are unclear. Herein we aimed to understand the expression of the IL-9 receptor and effects of IL-9 on the epithelium in EoE.

Methods: We used esophageal biopsies from pediatric EoE patients with active and inactive disease to analyze the expression of the IL-9 receptor, the adherens junction protein E-cadherin and the tight junction protein claudin-1. We treated primary human esophageal epithelial cells with IL-9 to understand its effects on E-cadherin expression and function.

Results: Active EoE subjects had increased epithelial expression of IL-9 receptor mRNA and protein (P < 0.05) and decreased membrane bound E-cadherin (P < 0.01) and claudin-1 (P < 0.05) expression. IL-9 receptor expression and mislocalized claudin-1 positively correlated and while membrane bound E-cadherin expression negatively correlated with the degree of histologic epithelial remodeling (P < 0.05). IL-9 decreased epithelial resistance in stratified primary human esophageal epithelial cells (P < 0.01) and membrane bound E-cadherin in epithelial cell monolayers (P < 0.01).

Conclusions: These data suggest that IL-9, its receptor, and its effects on E-cadherin may be important mechanisms for epithelial barrier disruption in EoE.

*Division of Allergy, Immunology

Division of Gastroenterology

Department of Pediatrics

§Department of Medicine

||Department of Pathology, University of California, San Diego and Rady Children's Hospital, San Diego, CA

Department of Physiology & Biophysics, Arkansas Children's Research Institute, University of Arkansas for Medical Sciences, Little Rock, AK.

Address correspondence and reprint requests to Seema S. Aceves, MD, PhD, Division of Allergy, Immunology, Departments of Pediatrics and Medicine, University of California, San Diego, 9500 Gilman Drive, MC-0760, La Jolla, CA 92093-0760 (e-mail:

Received 3 December, 2017

Accepted 3 June, 2018

A.D., R.K., and R.R. contributed equally to the data.

The study received funds from NIH/NIAID AI 092135 (S.S.A.), NIH/NIAID AI 135034 (S.S.A.), Rady Children's Hospital Academic Enrichment Grant (S.S.A.), NIH/NCRR/NCATS UL1TR000039 (R.C.K.).

The UCSD–RCHSD database is maintained by the Altman Clinical Research Institute at UCSD. The project described was partially supported by NIH grant UL1TR001442.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. S.A. and R.D. are co-inventors of oral viscous budesonide, patented by UCSD.

The authors report no conflicts of interest.

© 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,