Relevanz von Selenoproteinen in der Pathophysiologie chronisch-entzündlicher und maligner Darmerkrankungen
Zusammenfassung der Projektergebnisse
The essential trace element selenium (Se) is ingested with the diet and a sufficient intake required for optimal human health. Reduced Se levels are associated with chronic diseases of the gastrointestinal tract (GIT) in humans, e.g. colorectal cancer (CRC) and Crohn’s disease, and exacerbate experimental carcinogenesis and inflammation in the murine gut. Important mediators of selenium’s biological functions are selenoproteins, which are encoded by 25 genes in humans and which contain the 21st amino acid selenocysteine. A deeper understanding of the intestinal expression, functions and regulation of these proteins is required to identify their roles in intestinal carcinogenesis and inflammation and to be able to specifically target them for prevention and/or treatment of CRC and inflammatory bowel diseases. Within this project, I found that some selenoproteins (e.g. selenoprotein P (SeP), selenoprotein S (SelS) and glutathione peroxidase-4 (GPx-4)) are aberrantly expressed in ileal Crohn’s disease (CD). By analysing human gut sections, mRNA expression levels of SeP and GPx-4 were found to be particularly high in the ileum, as compared to the large bowel, whereas SelS mRNA was similarly expressed in these sections. Immunostainings revealed that SeP localises to epithelial cells in the small and large bowel of rats. In the large bowel, SeP was uniformly distributed among epithelial cells in crypts, and we also mapped intense staining of SeP to plasma cells located in the colon and in the spleen. In the small bowel, protein expression of SeP increased along the crypt-to-villus axis of the intestinal epithelium. This finding is consistent with transcriptional induction of SeP during enterocytic differentiation, as we have shown before. Additional selenoproteins were found here to be affected by enterocytic differentiation of Caco-2 cells, e.g. selenoprotein N, W and selenophosphate synthetase-2. Polarised Caco-2 cells secreted SeP exclusively via their basolateral membrane, which points to role of SeP in Se transport within the small bowel. SelS was found in the human and murine small and large bowel. Its protein expression was particularly high in macrophages and in Paneth cells, which are located in crypts of the small intestinal epithelium. These cells secrete large amounts of antimicrobial peptides and their dysfunction has been linked to Crohn’s disease. Previous studies have suggested that SelS is involved in maintaining endoplasmic reticulum (ER) homeostasis. Using a pharmacological inhibitor that interferes with ER function and by RNA interference-mediated silencing of SelS protein expression I have shown that SelS is regulated by but not a regulator of ER stress in colon-derived epithelial cell lines. Also, it did not affect cell death induced by oxidative stress in these cells. The function of SelS in the GIT and in Paneth Cells will be assessed in future studies.
Projektbezogene Publikationen (Auswahl)
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(2013). Intestinal selenoprotein P in epithelial cells and in plasma cells. Arch. Biochem. Biophys. [Epub ahead of print]
Bodo Speckmann, Hans-Jürgen Bidmon, Andrea Borchardt, Helmut Sies, Holger Steinbrenner
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(2013). Toward understanding success and failure in the use of selenium for cancer prevention. Antiox. Redox Signal. Epub 2013 Mar 21
Holger Steinbrenner, Bodo Speckmann, Helmut Sies
