Interleukin-13 (IL-13)/IL-13 receptor α1 (IL-13Rα1) signaling regulates intestinal epithelial cystic fibrosis transmembrane conductance regulator channel-dependent Cl^- secretion

Interleukin-13 (IL-13) has been linked to the pathogenesis of inflammatory diseases of the gastrointestinal tract. It is postulated that IL-13 drives inflammatory lesions through the modulation of both hematopoietic and nonhematopoietic cell function in the intestine. To delineate the relevant contribution of elevated levels of intestinal IL-13 to intestinal structure and function, we generated an intestinal IL-13 transgenic mouse (iIL-13Tg). We show that constitutive overexpression of IL-13 in the small bowel induces modification of intestinal epithelial architecture (villus blunting, goblet cell hyperplasia, and increased epithelial proliferation) and epithelial function (altered basolateral → apical Cl^- ion conductance). Pharmacological analyses in vitro and in vivo determined that elevated Cl ^- conductance is mediated by altered cystic fibrosis transmembrane conductance regulator expression and activity. Generation of iIL-13Tg/Il13rα1^-/-, iIL-13Tg/Il13rα2^-/-, and iIL-13Tg/Stat6^-/- mice revealed that IL-13-mediated dysregulation of epithelial architecture and Cl^- conductance is dependent on IL-13Rα1 and STAT-6. These observations demonstrate a central role for the IL-13/IL-13Rα1 pathway in the regulation of intestinal epithelial cell Cl^- secretion via up-regulation of cystic fibrosis transmembrane conductance regulator, suggesting an important role for this pathway in secretory diarrhea.