Glucocorticoid-regulated genes in eosinophilic esophagitis: a role for FKBP51.
BACKGROUND
Eosinophilic esophagitis (EE) involves marked accumulation of eosinophils in the esophageal mucosa that responds to swallowed fluticasone propionate (FP) in a subset of patients.


OBJECTIVE
We aimed to uncover the mechanism of action of swallowed FP in patients with EE by providing evidence for a topical effect in the esophagus by identifying a molecular signature for FP exposure in vivo.


METHODS
Global microarray expression profiles, immunofluorescence microscopy, and cell signaling in esophageal tissue and cell lines were analyzed.


RESULTS
Thirty-two transcripts exhibited altered expression in patients who responded to swallowed FP treatment. Esophageal FK506-binding protein 5 (FKBP51) mRNA levels were increased (P < .05) in FP responders compared with those seen in control subjects and patients with untreated active EE. After FP treatment of esophageal epithelial cells, FKBP51 mRNA and protein levels were increased in a dose- and time-dependent manner by FP treatment in vitro. FP-induced FKBP51 was steroid receptor dependent because RU486 completely inhibited gene and protein induction. The half-life of FKBP51 mRNA was 16 to 18 hours independent of FP treatment. FKBP51 overexpression reduced FP action as assessed by FP inhibition of IL-13-induced eotaxin-3 promoter activity.


CONCLUSIONS
Our results suggest that swallowed glucocorticoid treatment directly affects esophageal gene expression in patients with EE. In particular, increased FKBP51 transcript levels identify glucocorticoid exposure in vivo and distinguish FP responders from untreated patients with active EE and patients without EE. In addition, FKBP51 reduces glucocorticoid-mediated inhibition of IL-13 signaling in epithelial cells in vitro, suggesting that FKBP51 might influence FP responsiveness. We propose that esophageal FKBP51 levels have diagnostic and prognostic significance in patients with EE.
Caldwell
Julie M
JM
Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Blanchard
Carine
C
Collins
Margaret H
MH
Putnam
Philip E
PE
Kaul
Ajay
A
Aceves
Seema S
SS
Bouska
Catherine A
CA
Rothenberg
Marc E
ME
D000293:Adolescent; D000730:Androstadienes / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004802:Eosinophilia / Q000188:drug therapy*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D004941:Esophagitis / Q000188:drug therapy*; D004947:Esophagus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D000068298:Fluticasone; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007223:Infant; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult; D000099159:Tacrolimus Binding Protein 5
D000730:Androstadienes; D000068298:Fluticasone; D005938:Glucocorticoids; D018793:Interleukin-13; D011506:Proteins; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5