Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis.

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
The Journal of Immunology (Impact Factor: 5.36). 03/2010; 184(7):4033-41. DOI: 10.4049/jimmunol.0903069
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Carine Blanchard, Jul 07, 2015
  • Source
    • "Interestingly, several studies have shown FLG mutations confer a substantial risk for other atopic disorders recognized as Th2 polarized diseases including allergic rhinitis, IgEmediated peanut allergy, and eosinophilic esophagitis. These associations were observed even after controlling for co-existent AD (Blanchard et al., 2010; Brown et al., 2011b; Weidinger et al., 2008). This is a bit difficult to understand as FLG immunostaining is restricted to skin, oral mucosa and the cornified epithelium of the nasal vestibule with no detectable staining observed in epithelium from bronchial biopsies as well as gastrointestinal epithelium (De Benedetto et al., 2008; Weidinger et al., 2008; Ying et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: For at least half a century, noninvasive techniques have been available to quantify skin barrier function, and these have shown that a number of human skin conditions and disorders are associated with defects in skin permeability. In the past decade, several genes responsible for skin barrier defects observed in both monogenetic and complex polygenic disorders have been elucidated and functionally characterized. This has led to an explosion of work in the past 6 years that has identified pathways connecting epidermal barrier disruption and antigen uptake, as well as the quality and/or magnitude of the antigen-specific adaptive immune response. This review will introduce the notion that diseases arise from the dynamic crosstalk that occurs between skin barrier and the immune system using atopic dermatitis or eczema as the disease prototype. Nevertheless, the concepts put forth are highly relevant to a number of antigen-driven disorders for which skin barrier is at least transiently compromised, such as psoriasis, allergic contact dermatitis, and blistering disorders.
    Journal of Investigative Dermatology 01/2012; 132(3 Pt 2):949-63. DOI:10.1038/jid.2011.435 · 6.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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 approximately 6- and approximately 10-fold, respectively, in tissues from patients with EoE and approximately 3- and approximately 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.
    Gastroenterology 04/2010; 139(1):182-93.e7. DOI:10.1053/j.gastro.2010.03.057 · 13.93 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Organism-environment interfaces play an essential role in nutriment and gas exchanges. While accomplishing this function, interface tissues must cope with a bacterial, viral and toxic burden. A complex network of interactions between epithelia and immune cells deals with the matter of beneficial versus potentially dangerous signals, resulting in the crucial decision of tolerance induction or breaking. Apart from skin, airway and gastrointestinal epithelia are probably the most important sites of tolerance or sensitisation induction. Because of the complex epithelial–immune cell interplay, experimental settings addressing one cell type are often too simplistic; conversely, ethical as well as methodological issues hamper data collection in humans. Therefore, experimental studies on human complex multicellular in vitro systems should unveil new aspects of the cellular crosstalk in interface tissues.
    Revue Française d Allergologie 09/2010; 50(5):460-464. DOI:10.1016/j.reval.2010.06.010 · 0.22 Impact Factor