1. TCF-1-mediated Wnt signaling regulates Paneth cell innate immune defense effectors HD-5 and -6: implications for Crohn's disease.
- Author
-
Beisner J, Teltschik Z, Ostaff MJ, Tiemessen MM, Staal FJ, Wang G, Gersemann M, Perminow G, Vatn MH, Schwab M, Stange EF, and Wehkamp J
- Subjects
- Adolescent, Animals, Binding Sites, Caco-2 Cells, Female, HEK293 Cells, Humans, Ileum metabolism, Ileum pathology, Jejunum metabolism, Jejunum pathology, Male, Mice, Mice, Inbred C57BL, Organ Specificity, Protein Precursors genetics, Protein Precursors metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, T Cell Transcription Factor 1 chemistry, T Cell Transcription Factor 1 genetics, alpha-Defensins genetics, beta Catenin genetics, beta Catenin metabolism, Crohn Disease metabolism, Paneth Cells metabolism, T Cell Transcription Factor 1 metabolism, Wnt Signaling Pathway, alpha-Defensins metabolism
- Abstract
Wnt signaling regulates small intestinal stem cell maintenance and Paneth cell differentiation. In patients with ileal Crohn's disease (CD), a decrease of Paneth cell α-defensins has been observed that is partially caused by impaired TCF-4 and LRP6 function. Here we show reduced expression of the Wnt signaling effector TCF-1 (also known as TCF-7) in patients with ileal CD. Reporter gene assays and in vitro promoter binding analysis revealed that TCF-1 activates α-defensin HD-5 and HD-6 transcription in cooperation with β-catenin and that activation is mediated by three distinct TCF binding sites. EMSA analysis showed binding of TCF-1 to the respective motifs. In ileal CD patients, TCF-1 mRNA expression levels were significantly reduced. Moreover, we found specifically reduced expression of active TCF-1 mRNA isoforms. Tcf-1 knockout mice exhibited reduced cryptdin expression in the jejunum, which was not consistently seen at other small intestinal locations. Our data provide evidence that TCF-1-mediated Wnt signaling is disturbed in small intestinal CD, which might contribute to the observed barrier dysfunction in the disease., (Copyright © 2014 the American Physiological Society.)
- Published
- 2014
- Full Text
- View/download PDF