The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4.

The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4. Research Abstract Details 

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The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4. Abstract Text:

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

Ileal Crohn's disease (CD), a chronic mucosal inflammation, is characterized by two pertinent features: a specific decrease of Paneth cell-produced antimicrobial alpha-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 alpha-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 alpha-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 alpha-defensin levels and bacterial killing activity. Finally, the association between Paneth cell alpha-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 Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4. Publishing Authors By Initials

J Wehkamp,G Wang,I ,S Nuding,A Gregorieff,A Schnabel,RJ Kays,K Fellermann,O Burk,M Schwab,H Clevers,CL Bevins,EF Stange,

For similar peptides: antimicrobial cationic peptides: defensins: alpha-defensins research abstracts see: peptides: antimicrobial cationic peptides: defensins: alpha-defensins research

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The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of immunology (Baltimore, Md. : 1950)

VOLUME: 179

Page Numbers: 3109-18

Journal Abbreviation: J. Immunol.

ISSN: 0022-1767

DAY: 1

MONTH: Sep

YEAR: 2007

The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985117

The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4. Keywords Mesh Terms:

KEYWORDS: alpha-Defensins

MESH TERMS: genetics

Chemical & Substance for Abstract: The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4. Information

Substance Name: alpha-defensin 6, human

Registry Number: 0

Grant and Affiliation Information for The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4.

AFFILIATION: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tübingen, Auerbachstrasse 12, Stuttgart, Germany. jan.wehkamp@ikp-stuttgart.de

Country: United States

AGENCY: United States NIAID

GRANT: AI 50843

ACRONYM: AI

MEDLINETA: J Immunol

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