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

2010; Elsevier BV; Volume: 139; Issue: 1 Linguagem: Inglês

10.1053/j.gastro.2010.03.057

1528-0012

Xiang Zhu, Meiqin Wang, Parm Mavi, Madhavi Rayapudi, Akhilesh Kumar Pandey, Ajay Kaul, Philip E. Putnam, Marc E. Rothenberg, Anil Mishra,

IL-33, ST2, and ILC Pathways

Background & AimsQuantitative 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.MethodsQuantitative 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.ResultsQuantitative 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.ConclusionsIL-15 mediates in the pathogenesis of EoE. IL-15 activates CD4+ T cells to produce cytokines that act on eosinophils. 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. 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. 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. IL-15 mediates in the pathogenesis of EoE. IL-15 activates CD4+ T cells to produce cytokines that act on eosinophils.