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Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease

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Abstract

Loss of intestinal mucosa integrity is an important factor in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to characterize expression changes and allelic variants of genes related to intestinal epithelial barrier function in this disease. Therefore, ileal and colonic mucosal biopsies from nonaffected regions of patients with ulcerative colitis (UC) and Crohn’s disease (CD), as well as non-IBD probands, were subjected to Affymetrix DNA-microarray analysis. Real-time reverse transcription polymerase chain reaction was used for verification in larger IBD sample numbers. Disturbed mRNA expression was identified for several mucin genes in both disease groups and tissues. A significant downregulation in the colon was obtained for MUC2 in CD and MUC12 in CD and UC. Expression analysis of all dysregulated mucins in a broad human tissue panel revealed dominant epithelial tissue-specific transcription. In silico analysis of the regulatory regions of these mucins indicated nuclear factor κB (NFκB) binding sites in each promoter. Furthermore, NFκB was overrepresented in mucin promoters and a component of a specific combination of transcription factors (composite module). In vivo stimulation experiments in the adenocarcinoma cell line LS174T showed inducible mucin expression by the cytokines tumor necrosis factor-α and transforming growth factor-β, which could be blocked by NFκB signaling inhibitors. Allelic discrimination screening obtained statistically significant associations for the MUC2–V116M (P = 0.003) polymorphism with CD and for MUC4–A585S (P = 0.025), as well as MUC13–R502S (P = 0.0003) with UC. These data suggest that the disturbed expression of mucin genes and the connection to the NFκB pathway may influence the integrity of the intestine and therefore contribute to the pathophysiology of IBD.

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Acknowledgements

This work was supported by a grant from the Deutsche Forschungsgemeinschaft SFB585-A1 and the Dietmar Hopp Foundation. We thank Bettina Hartl, Manfred Haas, Steffanie Ebert, and Cornelia Hasenknopf for outstanding technical assistance. Parts of software and databases used in this work were funded by a grant of the German Ministry of Education and Research together with BioRegioN GmbH “BioProfil,” grant no. 0313092; EU grants: “TRANSISTOR” and INTAS grant No:03-51-5218, as well as by BIOBASE GmbH.

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Authors and Affiliations

  1. Institut für Klinische Chemie und Laboratoriumsmedizin, Universitätsklinikum Regensburg, Franz-Josef-Strauß-Allee 11, 93042, Regensburg, Germany

    Christoph Moehle, Nikolaus Ackermann, Thomas Langmann, Charalampos Aslanidis, Anna Schmitz-Madry & Gerd Schmitz

  2. Institute of Internal Medicine IV, University of Heidelberg, 69115, Heidelberg, Germany

    Nikolaus Ackermann, Alexandra Zahn & Wolfgang Stremmel

  3. BIOBASE GmbH, 38304, Wolfenbuettel, Germany

    Alexander Kel & Olga Kel-Margoulis

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  1. Christoph Moehle
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Correspondence to Gerd Schmitz.

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Christoph Moehle and Nikolaus Ackermann contributed equally to the work.

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ESM Table 1

Composite Module analysis result of human promoters. Displayed are the scores of each TF matrix and the overall composite score. (PDF 1815 kb)

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Moehle, C., Ackermann, N., Langmann, T. et al. Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease. J Mol Med 84, 1055–1066 (2006). https://doi.org/10.1007/s00109-006-0100-2

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