The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.
The Paneth Cell α-Defensin Deficiency of Ileal Crohn’s Disease Is Linked to Wnt/Tcf-4
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.
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Cites
Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease
Hugot, J.-P., Chamaillard, M., Zouali, H., Lesage, S., Cézard, J.-P., Belaiche, J., Almer, S., Tysk, C., O'Morain, C. A., Gassull, M., et al. (2001) · Nature · doi:10.1038/35079107 · Cited by 5,591
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A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease
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Hooper, L. V., & Gordon, J. I. (2001) · Science · doi:10.1126/science.1058709 · Cited by 2,362
Nod2-Dependent Regulation of Innate and Adaptive Immunity in the Intestinal Tract
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Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4
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Self-citationDarfeuille-Michaud, A., Boudeau, J., Bulois, P., Neut, C., Glasser, A.-L., Barnich, N., Bringer, M.-A., Swidsinski, A., Beaugerie, L., & Colombel, J.-F. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.04.061 · Cited by 1,566
Symbiotic bacteria direct expression of an intestinal bactericidal lectin
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Mucosal flora in inflammatory bowel disease
Swidsinski, A., Ladhoff, A., Pernthaler, A., Swidsinski, S., Loening–Baucke, V., Ortner, M., Weber, J., Hoffmann, U., Schreiber, S., Dietel, M., et al. (2002) · Gastroenterology · doi:10.1053/gast.2002.30294 · Cited by 1,346
Cited by
Microbial Influences in Inflammatory Bowel Diseases
Sartor, R. B. (2008) · Gastroenterology · doi:10.1053/j.gastro.2007.11.059 · Cited by 1,927
Unravelling the effects of the environment and host genotype on the gut microbiome
Spor, A., Koren, O., & Ley, R. (2011) · Nature Reviews Microbiology · doi:10.1038/nrmicro2540 · Cited by 1,509
Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis
Bevins, C. L., & Salzman, N. H. (2011) · Nature Reviews Microbiology · doi:10.1038/nrmicro2546 · Cited by 1,238
Self-citationIntestinal Barrier Dysfunction, LPS Translocation, and Disease Development
Ghosh, S. S., Wang, J., Yannie, P. J., & Ghosh, S. (2020) · Journal of the Endocrine Society · doi:10.1210/jendso/bvz039 · Cited by 759
Paneth Cells: Maestros of the Small Intestinal Crypts
Clevers, H. C., & Bevins, C. L. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183744 · Cited by 699
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Metadata
- Authors
- 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.
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-09-01
- Volume
- 179
- Issue
- 5
- Pages
- 3109-3118
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2112567807
- Cited by
- 286
- References
- 40
- FWCI
- 11.89
- Type
- journal article
- Language
- en
- Open access
- closed
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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. The Journal of Immunology. https://doi.org/10.4049/jimmunol.179.5.3109
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