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.

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.

• Authors: Michael Scharl, Sandra Frei, Theresa Pesch, Silvia Kellermeier, Joba Arikkat, Pascal Frei, Michael Fried, Achim Weber, Ekkehard Jehle, Anne Rühl, Gerhard Rogler
• Journal: Gut (Gut) Vol. 62 Issue 1 Pg. 63-72 (Jan 2013) ISSN: 1468-3288 [Electronic] England
• PMID: 22287592 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Integrin beta Chains
• Interleukin-13
• SNAI1 protein, human
• Snail Family Transcription Factors
• Transcription Factors
• Transforming Growth Factor beta
• integrin beta6

Topics

• Adult
• Biomarkers (metabolism)
• Blotting, Western
• Case-Control Studies
• Colitis, Ulcerative (metabolism)
• Crohn Disease (complications, metabolism, pathology)
• Female
• Fibroblasts (metabolism, pathology)
• HT29 Cells
• Humans
• Integrin beta Chains (metabolism)
• Interleukin-13 (metabolism)
• Intestinal Fistula (etiology, metabolism, pathology)
• Intestinal Mucosa (metabolism, pathology)
• Male
• Middle Aged
• Real-Time Polymerase Chain Reaction
• Snail Family Transcription Factors
• Transcription Factors (metabolism)
• Transforming Growth Factor beta (metabolism)