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Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2017 Sep 01; Vol. 199 (5), pp. 1886-1897. Date of Electronic Publication: 2017 Jul 26. - Publication Year :
- 2017
-
Abstract
- TNF plays an integral role in inflammatory bowel disease (IBD), as evidenced by the dramatic therapeutic responses in Crohn's disease (CD) patients induced by chimeric anti-TNF mAbs. However, treatment of CD patients with etanercept, a decoy receptor that binds soluble TNF, fails to improve disease. To explore this discrepancy, we investigated the role of TNF signaling in Wnt/β-catenin-mediated intestinal stem cell and progenitor cell expansion in CD patients, human cells, and preclinical mouse models. We hypothesized that TNF exerts beneficial effects on intestinal epithelial cell (IEC) responses to injury. In CD patients, intestinal stem cell and progenitor cell Wnt/β-catenin signaling correlates with inflammation status. TNF-deficient ( Tnf <superscript>-/-</superscript> ) mice exhibited increased apoptosis, less IEC proliferation, and less Wnt signaling when stimulated with anti-CD3 mAb. Bone marrow (BM) chimera mice revealed that mucosal repair depended on TNF production by BM-derived cells and TNFR expression by radioresistant IECs. Wild-type→ Tnfr1/2 <superscript>-/-</superscript> BM chimera mice with chronic dextran sodium sulfate colitis exhibited delayed ulcer healing, more mucosal inflammation, and impaired Wnt/β-catenin signaling, consistent with the hypothesis that epithelial TNFR signaling participates in mucosal healing. The direct effect of TNF on stem cells was demonstrated by studies of TNF-induced Wnt/β-catenin target gene expression in murine enteroids and colonoid cultures and TNF-induced β-catenin activation in nontransformed human NCM460 cells (TOPFlash) and mice (TOP-GAL). Together, these data support the hypothesis that TNF plays a beneficial role in enhancing Wnt/β-catenin signaling during ulcer healing in IBD. These novel findings will inform clinicians and therapeutic chemists alike as they strive to develop novel therapies for IBD patients.<br /> (Copyright © 2017 by The American Association of Immunologists, Inc.)
- Subjects :
- Animals
Antibodies, Monoclonal metabolism
Cell Line
Dextran Sulfate
Humans
Inflammatory Bowel Diseases therapy
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptors, Tumor Necrosis Factor, Type I genetics
Receptors, Tumor Necrosis Factor, Type II genetics
Signal Transduction
Tumor Necrosis Factor-alpha genetics
Wnt Proteins metabolism
Wound Healing
beta Catenin metabolism
Adult Stem Cells physiology
Antibodies, Monoclonal therapeutic use
Colitis immunology
Epithelial Cells physiology
Inflammatory Bowel Diseases immunology
Intestinal Mucosa physiology
Tumor Necrosis Factor-alpha metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 199
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 28747340
- Full Text :
- https://doi.org/10.4049/jimmunol.1601066