Eighth Annual BMRP Investigator Meeting
Pathomechanisms of Fistula Formation in Crohn’s Disease Patients
Michael Scharl1, Silvia Kellermeier1, Theresa Pesch1, Jann Wieler1, Colette Hemsley1, Angelina Meier1, Ekkehard Jehle3, Martin Hausmann1,2 and Gerhard Rogler1,2,a
1Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital; 2 ZIHP, Center of Integrative Human Physiology, University of Zurich (Zurich, Switzerland); 3 Department of Surgery, Klinikum Ravensburg (Germany)
The development of fistulae is a common complication in patients with Crohn’s disease with a cumulative incidence between 33% and 50%. As the pathogenesis of fistula formation is unknown and treatment success is limited. Recently we showed that a major part of those fistulae develop via epithelial mesenchymal transition (EMT) of intestinal epithelial cells. SNAIL1 is an important transcription factor during EMT.
We further characterized pathophysiological mechanisms in surgical specimens of fistula tracts and in cultured of isolated fistula myofibroblasts.
TGFbeta1 induced SNAIL1 mRNA expression in fistula myofibroblasts. Increased SNAIL1 protein expression was seen in fistula EMT cells and in the vicinity of fistula tracts. TNF antibodies reduced SNAIL1 expression by reducing TGFbeta secretion providing a potential mechanism for the beneficial effects of TNF antibodies on fistula healing. IL-13 has been suggested to be involved in fibrosis formation in CD. In PTPN2 knock-down cells, TNF treatment caused a significant increase in IL-13 secretion. TGF treatment caused a time- and dose-dependent decrease in PTPN2 protein. TGF further induced Dickkopf1 (DKK1) which blocks Wnt signalling and supports EMT.
Conclusion: Our data demonstrate that TNF increases, whereas TGF suppresses PTPN2 protein in fistula fibroblasts. Correspondingly, IL-13 secretion is increased, when PTPN2 levels are suppressed. TGF further induces SNAIL1 mRNA and protein expression as well as DKK1 and pushes EMT.
aPrincipal Investigator