The paneth cell α-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4

Jan Wehkamp, Guoxing Wang, Irmgard Kübler, Sabine Nuding, Alex Gregorieff, Anke Schnabel, Robert J. Kays, Klaus Fellermann, Oliver Burk, Matthias Schwab, Hans Clevers, Charles L Bevins, Eduard F. Stange

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203 Scopus citations

Abstract

Ileal Crohn's disease (CD), a chronic mucosal inflammation, is characterized by two pertinent features: a specific decrease of Paneth cell-produced antimicrobial α-defensins and the presence of mucosal-adherent bacteria. A mutation in NOD2, the muramyl dipeptide recognition receptor, is found in some patients, which leads to an even more pronounced α-defensin decrease. However, the underlying mechanism remains unclear for the majority of patients. In this study, we report a reduced expression in ileal CD of the Wnt-signaling pathway transcription factor Tcf-4, a known regulator of Paneth cell differentiation and α-defensin expression. Within specimens, the levels of Tcf-4 mRNA showed a high degree of correlation with both HD5 and HD6 mRNA. The levels of Tcf-4 mRNA were decreased in patients with ileal disease irrespective of degree of inflammation, but were not decreased in colonic CD or ulcerative colitis. As a functional indicator of Tcf-4 protein, quantitative binding analysis with nuclear extracts from small intestine biopsies to a Tcf-4 high-affinity binding site in the HD-5 and HD-6 promoters showed significantly reduced activity in ileal CD. Furthermore, a causal link was shown in a murine Tcf-4 knockout model, where the comparably reduced expression of Tcf-4 in heterozygous (+/-) mice was sufficient to cause a significant decrease of both Paneth cell α-defensin levels and bacterial killing activity. Finally, the association between Paneth cell α-defensins and Tcf-4 was found to be independent of the NOD2 genotype. This new link established between a human inflammatory bowel disease and the Wnt pathway/Tcf-4 provides a novel mechanism for pathogenesis in patients with ileal CD.

Original languageEnglish (US)
Pages (from-to)3109-3118
Number of pages10
JournalJournal of Immunology
Volume179
Issue number5
StatePublished - Sep 1 2007

ASJC Scopus subject areas

  • Immunology

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    Wehkamp, J., Wang, G., Kübler, I., Nuding, S., Gregorieff, A., Schnabel, A., Kays, R. J., Fellermann, K., Burk, O., Schwab, M., Clevers, H., Bevins, C. L., & Stange, E. F. (2007). The paneth cell α-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4. Journal of Immunology, 179(5), 3109-3118.