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Interleukin-13 and transforming growth factor β synergise in the pathogenesis of human intestinal fistulae
  1. Michael Scharl1,2,
  2. Sandra Frei1,
  3. Theresa Pesch1,
  4. Silvia Kellermeier1,
  5. Joba Arikkat1,
  6. Pascal Frei1,
  7. Michael Fried1,2,
  8. Achim Weber3,
  9. Ekkehard Jehle4,
  10. Anne Rühl5,
  11. Gerhard Rogler1,2
  1. 1Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
  2. 2Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
  3. 3Department of Pathology, Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland
  4. 4Department of Surgery, Oberschwaben-Klinik, Ravensburg, Germany
  5. 5Novartis Pharma AG, Basel, Switzerland
  1. Correspondence to Dr Michael Scharl, Division of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, Zurich 8091, Switzerland; michael.scharl{at}usz.ch

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.

Design 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.

  • IL-13
  • TGFβ
  • epithelial to mesenchymal transition
  • fistulae
  • Crohn's disease
  • inflammation
  • inflammatory bowel disease
  • IBD
  • IBD genetics
  • IBD basic research
  • gastroduodenal motility
  • gastroesophageal reflux disease
  • gastrointestinal motility
  • gastrointestinal peptides
  • cancer
  • oncogenes
  • gastric cancer
  • hepatocellular carcinoma
  • liver metastases
  • pancreatic pathology
  • pancreatic tumours
  • molecular pathology
  • gastrointestinal lymphoma
  • liver biopsy
  • abdominal surgery
  • macrophages
  • myofibroblasts
  • basic sciences
  • cell migration

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Footnotes

  • Funding This work was supported by an educational grant from Essex Chemie, Switzerland to MS, a research credit from the University of Zurich to MS, a grant from the Broad Medical Research Program to GR (grant no. IBD-0241R1), a grant from the Swiss National Science Foundation (grant no. 310030-120312) to GR, the Zurich Center for Integrative Human Physiology and the Swiss IBD cohort (SIBDC).

  • Competing interests None.

  • Ethics approval Ethics committee of the Canton Zurich, Switzerland.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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