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-Defensin Deficiency of Ileal Crohn’s Disease Is Linked to Wnt/Tcf-41
* Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany;
Department of Internal Medicine I, Robert Bosch Hospital, Stuttgart, Germany;
Department of Microbiology and Immunology, School of Medicine, University of California, Davis, CA 95616;
Hubrecht Laboratory, The Netherlands Institute of Developmental Biology, Utrecht, The Netherlands; and
¶ Department of Clinical Pharmacology, University of Tübingen, Tübingen, Germany
Ileal Crohn's disease (CD), a chronic mucosal inflammation, is characterized by two pertinent features: a specific decrease of Paneth cell-produced antimicrobial 
-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 -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 -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 -defensin levels and bacterial killing activity. Finally, the association between Paneth cell -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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Robert Bosch Foundation (Stuttgart, Germany), the Ernst Jung Foundation (Hamburg, Germany), the Deutsche Forschungsgemeinschaft, and the National Institutes of Health (AI32738 and AI50843), as well as the Deutsche Crohn und Colitis Vereinigung J.W. is an Emmy Noether Scholar of the Deutsche Forschungsgemeinschaft (WE 436/1-1).
2 Address correspondence and reprint requests to Dr. Jan Wehkamp, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, Stuttgart, Germany. E-mail address: jan.wehkamp{at}ikp-stuttgart.de
3 Abbreviations used in this paper: IBD, inflammatory bowel disease; CD, Crohn’s disease; HD, human defensin; UC, ulcerative colitis.
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