C V Neilsen1, P J Bryce. 1. Division of Allergy-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60610, USA.
Abstract
BACKGROUND: Eosinophilic oesophagitis (EE) is a clinico-pathologically defined oesophageal disorder that is characterized by eosinophil migration into oesophageal tissues. There is growing support for EE being an allergic disease and for a contribution of T-helper type 2 (Th2)-associated cytokines in disease pathogenesis. The respiratory system has been shown to be critical in driving the development of EE in animal models. However, the mechanisms underlying the recruitment of eosinophils into the oesophagus remain unclear. OBJECTIVE: We sought to investigate the influence of Th2-associated cytokines on the production of eosinophil-specific chemokines from the oesophagus directly. METHODS: In order to eliminate the potential involvement of the lung, we utilized isolated oesophageal rings. These were treated in vitro with IL-4 or IL-13 and the expression and production of CCL11 and CCL24 were determined. RESULTS: Our data demonstrate that IL-13 is a potent and direct inducer of both CCL11 and CCL24 production from the oesophagus, as is IL-4 also. The expression of CCL11 precedes CCL24 by several hours but then diminishes over time, as well as at high concentrations of IL-13. We demonstrate that there is an up-regulation of the inhibitory IL-13 receptor, IL-13Ralpha2 but that IL-13Ralpha1 remains unaltered. Oesophagus rings isolated from STAT6(-/-) mice were unable to produce CCL11 or CCL24 upon IL-13 treatment. Lastly, we demonstrate that oesophageal production of CCL11 and CCL24 upon IL-13 stimulation is sufficient to promote eosinophil migration. CONCLUSIONS: IL-13 is capable of directly stimulating oesophageal tissue to produce eosinophil-attracting chemokines and drive eosinophil migration.
BACKGROUND:Eosinophilic oesophagitis (EE) is a clinico-pathologically defined oesophageal disorder that is characterized by eosinophil migration into oesophageal tissues. There is growing support for EE being an allergic disease and for a contribution of T-helper type 2 (Th2)-associated cytokines in disease pathogenesis. The respiratory system has been shown to be critical in driving the development of EE in animal models. However, the mechanisms underlying the recruitment of eosinophils into the oesophagus remain unclear. OBJECTIVE: We sought to investigate the influence of Th2-associated cytokines on the production of eosinophil-specific chemokines from the oesophagus directly. METHODS: In order to eliminate the potential involvement of the lung, we utilized isolated oesophageal rings. These were treated in vitro with IL-4 or IL-13 and the expression and production of CCL11 and CCL24 were determined. RESULTS: Our data demonstrate that IL-13 is a potent and direct inducer of both CCL11 and CCL24 production from the oesophagus, as is IL-4 also. The expression of CCL11 precedes CCL24 by several hours but then diminishes over time, as well as at high concentrations of IL-13. We demonstrate that there is an up-regulation of the inhibitory IL-13 receptor, IL-13Ralpha2 but that IL-13Ralpha1 remains unaltered. Oesophagus rings isolated from STAT6(-/-) mice were unable to produce CCL11 or CCL24 upon IL-13 treatment. Lastly, we demonstrate that oesophageal production of CCL11 and CCL24 upon IL-13 stimulation is sufficient to promote eosinophil migration. CONCLUSIONS:IL-13 is capable of directly stimulating oesophageal tissue to produce eosinophil-attracting chemokines and drive eosinophil migration.
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