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A Role for Tumor Necrosis Factor and Bacterial Antigens in the Pathogenesis of Crohn's Disease–Associated Fistulae

Frei, Sandra Michaela MSc*; Pesch, Theresa*; Lang, Silvia*; Weber, Achim MD†,‡; Jehle, Ekkehard MD§; Vavricka, Stephan R. MD*,‡,‖; Fried, Michael MD*,‡; Rogler, Gerhard MD, PhD*,‡; Scharl, Michael MD*,‡

doi: 10.1097/01.MIB.0000435760.82705.23
Original Basic Science Articles

Background: Intestinal fistulae represent a severe complication of Crohn’s disease (CD). The authors have demonstrated that epithelial-to-mesenchymal transition plays a pivotal role in their pathogenesis. High levels of interleukin-13 and tumor necrosis factor (TNF) are detected in myofibroblast-like transitional cells covering the fistula tracts. Here, a functional role was investigated for the transcription factor Ets-1, TNF, and the bacterial wall component (muramyl dipeptide [MDP]) in the pathogenesis of CD-associated fistulae.

Methods: Perianal fistulae from CD patients were analyzed by immunohistochemistry. Primary colonic lamina propria fibroblasts (CLPFs) were isolated from CD patients with or without fistulizing disease. Messenger RNA (mRNA) levels were assessed by real-time polymerase chain reaction in CLPF or HT29 intestinal epithelial cells (IECs) grown as monolayers or spheroids.

Results: Strong expression of Ets-1 transcription factor was demonstrated in transitional cell covering the fistula tracts by immunohistochemistry. TNF induced mRNA expression of ETS-1 and β6-integrin in HT29 IEC and in CLPF from fistulizing CD patients. These effects could be fully blocked by administration of anti-TNF antibodies. In HT29 cells, TNF further induced mRNA levels of TNF and transforming growth factor beta by treatment for 24 hours. In fistula CLPF derived from CD patients, TNF induced expression of β6-integrin, TNF, and transforming growth factor beta. Of note, the bacterial wall component, MDP, induced mRNA levels of ETS-1, transforming growth factor beta, interleukin-13, SNAIL1, and β6-integrin in HT29 IEC monolayers and fistula CLPF by treatment for 24 hours.

Conclusions: TNF and MDP induce the expression of factors associated with epithelial-to-mesenchymal transition and invasion in IEC and fistula CLPF. Our findings indicate that TNF and MDP might synergize in the pathogenesis of CD-associated fistulae.

Article first published online 1 November 2013Supplemental Digital Content is Available in the Text.

*Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland;

Department of Pathology, Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland;

Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland;

§Department of Surgery, Oberschwaben-Klinik, Ravensburg, Germany; and

Division of Gastroenterology and Hepatology, Stadtspital Triemli, Zurich, Switzerland.

Reprints: Michael Scharl, MD, Division of Gastroenterology and Hepatology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland (e-mail:

Supported by a grant from Fonds zur Förderung des akademischen Nachwuchses (FAN) of the Zürcher Universitätsverein (ZUNIV) (to M.S.), a research grant from the Swiss Philanthropy Foundation (to M.S. and G.R.), a research credit from the University of Zurich (to M.S.), research grants from the Swiss National Science Foundation (Grant No. 314730-146204 to M.S.; Grant No. 310030-120312 to G.R.; Grant No. 320000-114009/1 to S.R.V.) and the Swiss IBD Cohort (Grant No. 3347CO-108792) and by the Zurich Center for Integrative Human Physiology of the University of Zurich.

The authors have no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Received August 21, 2013

Accepted September 17, 2013

© Crohn's & Colitis Foundation of America, Inc.
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