Volume 120, Issue 6 , Pages 1292-1300, December 2007
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 TH2 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 TH2 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.
Key words: IL-13, eosinophilic esophagitis, eotaxin-3, cytokines, esophageal epithelial cells, keratinocytes
Abbreviations used: EE, Eosinophilic esophagitis, ER, Estrogen receptor, FP, Fluticasone propionate, STAT6, Signal transducer and activator of transcription 6
Supported in part by National Institutes of Health grants AI070235 and AI45898 (M.E.R.), the Food Allergy and Anaphylaxis Network (M.E.R.), the Campaign Urging Research for Eosinophil Disorders, the Buckeye Foundation (M.E.R.), the Food Allergy Project (M.E.R.), the American Heart Association 0625296B (C.B.), the Thrasher Research Funds NR-0014 (C.B.), the Instituto Carlos III Fondo de Investigación Sanitaria CD05/00060 (M.V.), Public Health Service grant CA102357 (S.I.W.), the Translational Research Initiative, Cincinnati Children's Hospital Medical Center, and the DHC (NIDDK 064403).
Disclosure of potential conflict of interest: M. E. Rothenberg has consulting arrangements with Ception Therapeutics and Merck, owns stock in Ception Therapeutics, and is on the speakers' bureau for Merck. The rest of the authors have declared that they have no conflict of interest.
Transcript profiling is available online at http://cypher.cchmc.org:1104. The reader should login as a guest and select “HG-U133 genome”; experiments and gene lists are located in the folder named MRothenberg/blanchard et al.
PII: S0091-6749(07)01974-4
doi:10.1016/j.jaci.2007.10.024
© 2007 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Volume 120, Issue 6 , Pages 1292-1300, December 2007
