9th Annual BMRP Investigator Meeting - Abstract
New Insights in the Pathogenesis of Crohn’s Disease Associated Intestinal Fistulae
Michael Scharl1, Theresa Pesch1, Silvia Kellermeier1, Joba Arikkat1, Pascal Frei1, Achim Weber2, Alois Fürst3, Michael Fried1 and Gerhard Rogler1,a
1Division of Gastroenterology and Hepatology, Zurich Center for Integrative Human Physiology, 2Department of Pathology, Institute of Surgical Pathology, University Hospital and University of Zurich (Zurich, Switzerland); 3Department of Surgery, Caritas-Hospital St. Josef (Regensburg, Germany)
A common clinical complication of Crohn’s disease (CD) are fistulae, which are often recurring and non-responding to medical treatment. We have previously shown that epithelial to mesenchymal transition (EMT) may play a crucial role in the pathogenesis of CD fistulae. Transforming growth factor β (TGFβ), specific cytokines and the transcription factors SNAIL and SLUG have been associated with the onset of EMT in organ fibrosis. Variations of the PTPN2 gene have been associated with the risk to develop CD. We investigated a possible role for those factors in the pathogenesis of CD-associated fistulae.
While SNAIL1 was heavily expressed in the nuclei of fistula covering fibroblast like “transitional cells” (TCs), SLUG, FGF-1 and FGF-2 were rather detected in the fibrotic periphery of CD-fistulae than in TC. In fistula colonic lamina propria fibroblasts (CLPF), SNAIL1 levels were strongly increased compared to non-fistulae controls and could be further induced by TGFβ. SLUG expression was also elevated in fistulae CLPF (as were levels for b6-integrin and MMP-13), but was insensitive to TGFβ. TNF-blockers were able to prevent the TNF-induced secretion of TGFβ and IL-8 from fistula CLPF. In a cell model of HT29-spheroids TGFβ induced mRNA expression of SNAIL1, but decreased levels SLUG by 7 d treatment. A loss of PTPN2 expression was followed by increased SLUG induction. Stimulation of PTPN2 activity could reverse these effects.
SNAIL1 and TNF are strongly expressed in TC of CD-fistulae. TGFβ induces SNAIL1 expression in fistula CLPF and TNF-blocker prevent TNF-induced secretion of TGFβ. SLUG is not induced by TGFβ but by different mechanisms. These data indicate a role for SNAIL1 in the EMT of fistula lining cells. For invasiveness of fistulae an induction of SLUG by additional mechanisms seems to be mandatory. PTPN2 is involved in the regulation of expression of SLUG which may indicate a role in fistula progression.
a Principal Investigator