Coordinate Interaction between IL-13 and Epithelial Differentiation Cluster Genes in Eosinophilic Esophagitis

Abstract

We have previously proposed that the pathogenesis of eosinophilic esophagitis (EE) is mediated by an IL-13–driven epithelial cell response associated with marked gene dysregulation including eotaxin-3 overproduction. Herein, we compared epithelial responses between normal (NL) and EE patients aiming to uncover molecular explanations for EE pathogenesis. Esophageal epithelial cells could be maintained up to 5 passages, with 67% and 62% of cell lines reaching confluence in NL and EE, respectively. Both sets of epithelial cells avidly responded to IL-13 at similar levels as assessed by eotaxin-3 production. Acidic pH increased cellular release of eotaxin-3 (4.6 ± 1.98 ng/mL vs. 12.46 ± 2.90 ng/mL at pH 7.4 and 4 respectively, p<0.05). Numerous epidermal differentiation complex (EDC) genes, such as filaggrin, and SPRR3 were downregulated both in IL-13-stimulated esophageal epithelial cells and in EE biopsies compared to NL. While the filaggrin loss of function mutation 2282del4 was overrepresented in EE compared to control individuals (6.1% vs. 1.3% respectively, p=0.0172), the decreased filaggrin expression was uniformly seen in all EE patients in vivo. Indeed, expression of the EDC genes filaggrin and involucrin was strongly decreased directly by IL-13. These results establish that the epithelial response in EE involves a cooperative interaction between IL-13 and expression of EDC genes.

Gastrointestinal mucosal barrier function and diseases

“…The barrier function of esophageal mucosa in EoE might be regulated by Th2 cytokines and filaggrin [47,48].…”

Diagnosis and treatment of eosinophilic esophagitis in clinical practice

“…IL-13 and IL-15 induce the secretion of eotaxin-3 from epithelial cells, which is one of the strongest chemotactic factors for eosinophils [45]. IL-13 also attenuates the barrier function of the squamous epithelium by decreasing the gene expression of the epidermal differentiation complex (e.g., filaggrin or involucrin) [51]. Locally aggregated and activated eosinophils, in conjunction with mast cells, produce TGF-b1.…”

La mystérieuse œsophagite à éosinophiles garde encore quelques secrets

“…Ces molécules sont aussi connues comme étant directement impliquées dans la différentiation et/ou le recrutement des éosinophiles. On aa ussi montré que l'IL-13 avait des activitésd irectes sur les cellules épithéliales de l'oesophage qui pourraient expliquer certaines lésions et symptômes de l'EoE [32]. Et donc ces molécules ont été sélectionnées comme les premiers candidats potentiels pour développer de nouvelles thérapies de l'EoE, notamment à partir de modèles animaux prometteurs [33,34,31,35].…”