- Title
- Elevated IL-33 expression is associated with pediatric eosinophilic esophagitis, and exogenous IL-33 promotes eosinophilic esophagitis development in mice
- Creator
- Judd, L. M.; Heine, R. G.; Collison, A. M.; Mattes, J.; Allen, K. J.; Giraud, A. S.; Menheniott, T. R.; Buzzelli, J.; O'Brien-Simpson, N.; Pavlic, D.; O'Connor, L.; Al Gazali, K.; Hamilton, O.; Scurr, M.
- Relation
- NHMRC
- Relation
- American Journal of Physiology - Gastrointestinal and Liver Physiology Vol. 310, Issue 1, p. G13-G25
- Publisher Link
- http://dx.doi.org/10.1152/ajpgi.00290.2015
- Publisher
- American Physiological Society
- Resource Type
- journal article
- Date
- 2016
- Description
- We tested whether the T helper (Th) type 2 (Th2) cell agonist and allergenic ligand IL-33 was associated with eosinophilic esophagitis (EoE) development in a pediatric cohort and whether IL-33 protein could induce disease symptoms in mice. Biopsies from EoE patients or controls were used to measure IL-33 mRNA and protein expression. Increased expression of IL-33 mRNA was found in the esophageal mucosa in EoE. IL-33 protein was detected in cells negative for CD45, mast cells, and epithelial cell markers near blood vessels. Circulating levels of IL-33 were not increased. The time course for IL-33 gene expression was quantified in an established Aspergillus fumigatus allergen mouse model of EoE. Because IL-33 induction was transient in this model and chronicity of IL-33 expression has been demonstrated in humans, naive mice were treated with recombinant IL-33 for 1 wk and esophageal pathology was evaluated. IL-33 application produced changes consistent with phenotypically early EoE, including transmural eosinophilia, mucosal hyperproliferation, and upregulation of eosinophilic genes and chemokines. Th2 cytokines, including IL-13, along with innate lymphoid cell group 2, Th1/17, and M2 macrophage marker genes, were increased after IL-33 application. IL-33-induced eosinophilia was ablated in IL-13 null mice. In addition, IL-33 induced a profound inhibition of the regulatory T cell gene signature. We conclude that IL-33 gene expression is associated with pediatric EoE development and that application of recombinant protein in mice phenocopies the early clinical phase of the human disease in an IL-13-dependent manner. IL-33 inhibition of esophageal regulatory T cell function may induce loss of antigenic tolerance, thereby providing a mechanistic rationale for EoE development.
- Subject
- eosinophilic esophagitis; IL-33; food allergy; Th2
- Identifier
- http://hdl.handle.net/1959.13/1320197
- Identifier
- uon:24090
- Identifier
- ISSN:0193-1857
- Language
- eng
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