How the Interaction of Two Molecules Favors the Development of Crohn’s Disease

New findings on the developmental mechanism of chronic inflammatory bowel disease Crohn's disease published in "Gastroenterology"

Crohn's disease
The picture shows a biopsy of intestinal tissue (colon) of a Crohn's disease patient. Blue nuclei are stained, green T cells and red the CYLD molecule, yellow a colocalization of CYLD and T cells. The picture clearly shows an increased infiltration of pro-inflammatory T cells into the intestinal tissue of Crohn's disease patients. It is interesting that these cells also express the CYLD molecule more intensely. Source: Katharina Gerlach and Benno Weigmann

The interaction between the two proteins CYLD and SMAD7 in the gut plays a central role in the development of Crohn’s disease. This is what scientists from the University Medical Center Mainz have in common with colleagues from the Friedrich-Alexander-University Erlangen-Nürnberg and Dr. med. Elke Glasmacher of Helmholtz Zentrum München found out. They were able to show that a shortened variant of CYLD – in the jargon of sCYLD – interacts with SMAD7 and, as a result, induces a malfunction of the “transforming growth factor” (TGF) beta signaling pathway, which is crucial for Crohn’s disease. If it were possible to prevent the interaction of sCYLD and SMAD7, this could counteract the intestinal inflammation. The research findings were published in the renowned journal “Gastroenterology”.

Over 400,000 people in Germany suffer from Crohn’s disease. Symptoms include persistent diarrhea and spasmodic abdominal pain. Despite intensive research, the cause of this inflammatory bowel disease is not yet fully understood.

So far it has been known that the “TGF beta” signaling pathway has an anti-inflammatory effect and is centrally involved in preventing the development of Crohn’s disease. In addition, it has been proven that an increased presence of the molecule SMAD7 leads to disturbances in the “TGF beta” signaling pathway. SMAD7 is considered to be an antagonist of this signaling pathway, blocking the release of an anti-inflammatory messenger (TGF-b1). This leads to an increased activation of immune cells – such as T cells and macrophages – and can thus trigger an intestinal inflammation. SMAD7 is usually present in small amounts but is highly expressed in a variety of diseases, including cancer and Crohn’s disease.

Another molecule, CYLD, has been implicated in other research related to Crohn’s disease. CYLD was first discovered as a tumor suppressor, as a defect in the CYLD gene can lead to the development of various cancers. Several studies have now shown that malfunction of CYLD activity leads to increased inflammatory reactions and thus promotes the development of chronic inflammatory bowel inflammation. “Whether and how the two proteins SMAD7 and CYLD interact and how this affects the development of Crohn’s disease, however, was not known, and this was the aim of our work,” emphasizes the director of the Institute of Molecular Medicine at the University Medical Center Mainz, Univ. -prof. Dr. Ari Waisman, whose working group carried out the research. “In fact, we were able to show for the first time that the truncated form of CYLD – sCYLD – and SMAD7 interact to block the ‘TGF beta’ pathway. This in turn leads to inflammatory processes in the intestine. “

To the research findings came Professor Waisman and his team, in which they analyzed intestinal biopsies, inter alia, by means of fluorescence microscopy. “We have found an increased incidence of both sCYLD and SMAD7 in the inflammatory T-cells of the gut of patients with Crohn’s disease,” says lead author of the publication. Yilang Tang. “In addition, we were able to show that the interaction of both proteins also leads to a malfunction of important immune cells – such as regulatory T cells, which play an important role in the suppression of inflammatory reactions.” In fact, the TGF-beta signaling pathway is essential for the anti-inflammatory effect of regulatory T cells.

“Overall, our research finding demonstrates for the first time that not only is regulation of the ‘TGF beta’ signaling pathway via SMAD7 important in the treatment of Crohn’s disease. Rather, it is precisely the interaction of sCYLD with SMAD7 that plays a crucial role in the development of intestinal disease. ” Sonja Reissig, co-author of the research publication. Against this background, an innovative therapeutic approach for the treatment of Crohn’s disease patients may be either to inhibit the interaction of the proteins involved or to regulate the shortening of CYLD to sCYLD in order to counteract the development of sCYLD and thus the chronic inflammation in Crohn’s disease . “