title: Interleukin-13 and transforming growth factor β synergise in the pathogenesis of human intestinal fistulae.
abstract: OBJECTIVE
  Epithelial to mesenchymal transition (EMT) seems to play an important role in the pathogenesis of fistulae, a common clinical complication of Crohn's disease (CD). TGFβ and interleukin-13 (IL-13) have been correlated with the onset of EMT-associated organ fibrosis and high levels of TGFβ have been shown in transitional cells (TCs) lining CD fistula tracts. This study investigated whether IL-13 could be involved in the pathogenesis of CD-associated fistulae.
  
  
  METHODS
  Protein or mRNA levels in HT29 intestinal epithelial cells (IECs) or colonic lamina propria fibroblasts (CLPFs) were studied by western blotting or real-time PCR. CLPFs were isolated from non-inflammatory disease controls or patients with CD with or without fistulae and IL-13 levels were analysed in surgically removed fistula specimens by immunohistochemistry.
  
  
  RESULTS
  TGFβ induced IL-13 secretion in CLPFs from patients with fistulising CD. In fistula specimens high levels of IL-13 were detected in TCs covering fistula tracts. In HT29 IEC monolayers, IL-13 induced SLUG and β6-integrin mRNA, which are associated with cell invasion. HT29 spheroids completely disintegrated when treated with TGFβ for 7 days, whereas IL-13-treated spheroids did not show morphological changes. Here, TGFβ induced mRNA expression of SNAIL1 and IL-13, whereas IL-13 elevated SLUG and β6-integrin mRNA. An anti-IL-13 antibody was able to prevent IL-13-induced SLUG expression in HT29 IECs.
  
  
  CONCLUSIONS
  TGFβ induces IL-13 expression and an EMT-like phenotype of IECs, while IL-13 promotes the expression of genes associated with cell invasion. These findings suggest that TGFβ and IL-13 play a synergistic role in the pathogenesis of fistulae and inhibition of IL-13 might represent a novel therapeutic approach for fistula treatment.
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, Zurich 8091, Switzerland. michael.scharl@usz.ch
authors.forename: Michael
authors.initials: M
authors.lastname: Scharl
authors.forename: Sandra
authors.initials: S
authors.lastname: Frei
authors.forename: Theresa
authors.initials: T
authors.lastname: Pesch
authors.forename: Silvia
authors.initials: S
authors.lastname: Kellermeier
authors.forename: Joba
authors.initials: J
authors.lastname: Arikkat
authors.forename: Pascal
authors.initials: P
authors.lastname: Frei
authors.forename: Michael
authors.initials: M
authors.lastname: Fried
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Jehle
authors.forename: Anne
authors.initials: A
authors.lastname: Rühl
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rogler
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000378:metabolism; D003424:Crohn Disease / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D039641:Integrin beta Chains / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism*; D007412:Intestinal Fistula / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D039641:Integrin beta Chains; D018793:Interleukin-13; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C072170:integrin beta6