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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

242 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)3109-3118
Aantal pagina's10
TijdschriftJournal of Immunology
Volume179
Nummer van het tijdschrift5
DOI's
StatusGepubliceerd - 1 sep. 2007
Extern gepubliceerdJa

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