IL-13 Receptor α2 Promotes Epithelial Cell Regeneration From Radiation–Induced Small Intestinal Injury in Mice

Background & Aims: The cytokines interleukin (IL)-4 and IL-13 have pleiotropic effects on a variety of cell types and impact both pathologic changes and tissue remodeling. The aim of this study was to clarify the roles of IL-13 receptor α2 (IL-13Rα2), which is the high-affinity decoy receptor for IL-13, in gastrointestinal tract epithelial cell turnover and repair. Methods: We have compared the regenerative process following mucosal damage induced by whole-body 3-Gy X-ray irradiation of wild-type (WT) and IL-4 receptor α gene–deficient (IL-4R−/−) mice. Then we treated mice with IL-13Rα2 human immunoglobulin (Ig) chimeric protein. Results: Up-regulation of mRNA levels for IL-13 in NK cells in the lamina propria was seen after irradiation of WT mice. Concomitant with vigorous epithelial cell division in the jejunum following irradiation, expression of the IL-13Rα2 dramatically increased in myofibroblasts and fibroblasts. In contrast, epithelial cell repair was delayed in IL-4R−/− mice, which did not show transient up-regulation of IL-13Rα2, although up-regulation of IL-13 was seen. Addition of IL-13 but not IL-4 to primary cultures of small intestine from both WT and IL-4R−/− mice induced epithelial cell damage. Treatment of IL-4R−/− mice with IL-13Rα2-Ig resulted in increased numbers of dividing epithelial cells and improved tissue repair after irradiation. Further, treatment with IL-13Rα2-Ig increased numbers of microcolonies of regenerating epithelial cells in the intestine of WT mice after severe damage induced by 12-Gy irradiation. Conclusions: The IL-13Rα2 is a major regulatory factor involved in the regeneration of epithelial cells in the gastrointestinal tract.