Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis.
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. In this study, we compared epithelial responses between healthy patients and those with EE, aiming to uncover molecular explanations for EE pathogenesis. Esophageal epithelial cells could be maintained for up to five passages, with 67% and 62% of cell lines reaching confluence in healthy controls and EE cases, 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 versus 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 specimens compared with healthy controls. Whereas the filaggrin loss of function mutation 2282del4 was overrepresented in EE compared with control individuals (6.1% versus 1.3% respectively; p = 0.0172), the decreased filaggrin expression was uniformly seen in all EE cases 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.
Blanchard
Carine
C
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Stucke
Emily M
EM
Burwinkel
Karen
K
Caldwell
Julie M
JM
Collins
Margaret H
MH
Ahrens
Annette
A
Buckmeier
Bridget K
BK
Jameson
Sean C
SC
Greenberg
Allison
A
Kaul
Ajay
A
Franciosi
James P
JP
Kushner
Jonathan P
JP
Martin
Lisa J
LJ
Putnam
Philip E
PE
Abonia
J Pablo
JP
Wells
Suzanne I
SI
Rothenberg
Marc E
ME
D049109:Cell Proliferation; D002478:Cells, Cultured; D004802:Eosinophilia; D004847:Epithelial Cells / Q000378:metabolism*; D004941:Esophagitis / Q000235:genetics* / Q000378:metabolism*; D000091344:Filaggrin Proteins; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism*; D007381:Intermediate Filament Proteins / Q000096:biosynthesis* / Q000235:genetics; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic; D011498:Protein Precursors / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D018793:Interleukin-13; D007381:Intermediate Filament Proteins; D011498:Protein Precursors; C032253:involucrin