IL-13 involvement in eosinophilic esophagitis: Transcriptome analysis and reversibility with glucocorticoids.

Background: Eosinophilic esophagitis (EE) is an emerging worldwide disease that mimics gastroesophageal reflux disease. Early studies have established that esophageal eosinophilia occurs in association with T_H2 allergic responses, and we recently identified an EE-specific esophageal transcriptome that included eotaxin-3. Objective: We sought to determine the mechanism by which this T_H2 response leads to EE. Methods: Real-time PCR and microarray analysis were performed on RNA extracted from esophageal biopsy specimens and primary esophageal epithelial cell cultures stimulated with IL-13 (0-100 ng/mL). Transient transfections in esophageal cell lines were performed with plasmids containing the luciferase gene driven by eotaxin-3 promoter fragments and modified forms of signal transducer and activator of transcription 6. Results: The IL-13 mRNA level was markedly increased (16-fold) in esophageal biopsy specimens from patients with EE compared with those from healthy individuals. Furthermore, IL-13 treatment of primary esophageal epithelial cells was sufficient to induce a global-expression transcript profile that remarkably overlapped with the EE-specific esophageal transcriptome. In addition, esophageal epithelial cells markedly produce eotaxin-3 after IL-13 stimulation through a transcriptional mechanism dependent on signal transducer and activator of transcription 6. Lastly, increased IL-13 mRNA levels and the EE transcriptome were largely reversible with glucocorticoid treatment in vivo. Conclusions: Taken together, we propose that the pathogenesis of EE is mediated by an IL-13–stimulated keratinocyte-derived transcriptome that is largely reversible with corticosteroid treatment. Furthermore, we identify an in vivo IL-13–induced transcriptome that has potential utility for target assessment after anti-IL-13 therapeutics. Clinical implications: IL-13–induced pathways and genes are fundamental processes in the cause and manifestations of EE; as such, therapeutic agents that interfere with IL-13 might be particularly useful for disease treatment. [Copyright &y& Elsevier]