Eosinophilic esophagitis (EoE) is an emerging chronic allergen-driven inflammatory disease with a predilection for males (3:1). We sought to evaluate the molecular mechanisms underlying the male predilection in EoE.
Primary human esophageal fibroblasts from patients with EoE and healthy controls were harvested and treated ex vivo with IL-4, IL-13, or TGF-β1 and analyzed for mRNA expression of genes of interest by quantitative PCR. Esophageal biopsy specimens from EoE patients were evaluated by immunohistochemistry.
Immunohistochemical staining of esophageal biopsies from our EoE cohort (N = 138 patients; 110 males and 28 females) demonstrated significantly more TGF-β1-positive cells in female than male patients (p<0.001) but no difference in phosphorylated-SMAD2/3 expression, suggesting a potential cell-intrinsic differential response to TGF-β1 signaling. Primary human esophageal fibroblasts from age- and race-matched EoE and healthy male esophagi responded to TGF-β1 stimulation with more α-sma and col1α1 mRNAs than female cells (EoE group: p<0.0001 and p<0.001, respectively; healthy controls: p< 0.0001 and p<0.01, respectively). Treatment of normal or EoE primary human esophageal fibroblasts derived from males with IL-4 or IL-13 ex vivo induced significantly more ccl26 mRNA when compared with female fibroblasts (healthy controls: p< 0.0001 for each; EoE IL-13: p<0.05).
Our data suggest that, compared to female fibroblasts, male esophageal fibroblasts preferentially respond to Th2 cytokines with an augmented eosinophilic chemotactic milieu and are additionally skewed toward a profibrotic phenotype. Our data indicate that intrinsic sex-specific differences in primary human esophageal fibroblasts may contribute to the male predilection in EoE.