The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4.
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.
Wehkamp
Jan
J
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tübingen, Auerbachstrasse 12, Stuttgart, Germany. jan.wehkamp@ikp-stuttgart.de
Wang
Guoxing
G
Kübler
Irmgard
I
Nuding
Sabine
S
Gregorieff
Alex
A
Schnabel
Anke
A
Kays
Robert J
RJ
Fellermann
Klaus
K
Burk
Oliver
O
Schwab
Matthias
M
Clevers
Hans
H
Bevins
Charles L
CL
Stange
Eduard F
EF
D000818:Animals; D003424:Crohn Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007079:Ileitis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D019879:Paneth Cells / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D023084:alpha-Defensins / Q000172:deficiency* / Q000235:genetics
C500225:DEFA5 protein, human; C517765:DEFA6 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D023084:alpha-Defensins