title: Interleukin-13 (IL-13)/IL-13 receptor alpha1 (IL-13Ralpha1) signaling regulates intestinal epithelial cystic fibrosis transmembrane conductance regulator channel-dependent Cl- secretion.
abstract: 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.
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wu
authors.forename: Richard
authors.initials: R
authors.lastname: Ahrens
authors.forename: Heather
authors.initials: H
authors.lastname: Osterfeld
authors.forename: Taeko K
authors.initials: TK
authors.lastname: Noah
authors.forename: Katherine
authors.initials: K
authors.lastname: Groschwitz
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.forename: Kris A
authors.initials: KA
authors.lastname: Steinbrecher
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.forename: Noah F
authors.initials: NF
authors.lastname: Shroyer
authors.forename: Klaus I
authors.initials: KI
authors.lastname: Matthaei
authors.forename: Fred D
authors.initials: FD
authors.lastname: Finkelman
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hogan
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002712:Chlorides / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D003560:Cysts / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003967:Diarrhea / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000235:genetics / Q000378:metabolism*; D007410:Intestinal Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D017136:Ion Transport / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D002712:Chlorides; C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D019005:Cystic Fibrosis Transmembrane Conductance Regulator