Interleukin-15 Expression Is Increased in Human Eosinophilic Esophagitis and Mediates Pathogenesis in Mice

Background & Aims Quantitative microarray analyses have shown increased expression of interleukin-15 ( IL-15 ) messenger RNA in the esophagus of patients with eosinophilic esophagitis (EoE), a recently recognized allergic disorder with poorly understood pathogenesis. Methods Quantitative polymerase chain reaction and enzyme-linked immunosorbent assay analyses were performed to examine protein and transcript levels in tissue samples from patients with EoE. Tissues from IL-15Ra –deficient and wild-type (control) mice were also examined. Tissue eosinophilia was determined by immunostaining for major basic protein and flow cytometry for cell-surface receptors. Results Quantitative polymerase chain reaction analyses showed that levels of IL-15 and its receptor IL-15Ra were increased ∼6- and ∼10-fold, respectively, in tissues from patients with EoE and ∼3- and ∼4-fold, respectively, in mice with allergen-induced EoE. A >2-fold increase in serum IL-15 protein levels was also detected in human EoE samples compared with those from healthy individuals. Human IL-15 messenger RNA levels correlated with esophageal eosinophilia ( P < .001). IL-15Ra –deficient mice were protected from allergen-induced esophageal eosinophilia compared with controls ( P < .001), even though similar levels of airway eosinophilia were observed in all mice. IL-15 activated STAT5 and CD4+ T cells to produce cytokines that act on eosinophils. Incubation of primary esophageal epithelial cells from mice and humans with IL-15 caused a dose-dependent increase in the mRNA expression and protein levels of eotaxin-1, -2, and -3. Conclusions IL-15 mediates in the pathogenesis of EoE. IL-15 activates CD4+ T cells to produce cytokines that act on eosinophils.