TY - JOUR
T1 - Epithelial TNF receptor signaling promotes mucosal repair in inflammatory bowel disease
AU - Bradford, Emily M.
AU - Ryu, Stacy H.
AU - Singh, Ajay Pal
AU - Lee, Goo
AU - Goretsky, Tatiana
AU - Sinh, Preetika
AU - Williams, David B.
AU - Cloud, Amber L.
AU - Gounaris, Elias
AU - Patel, Vihang
AU - Lamping, Olivia F.
AU - Lynch, Evan B.
AU - Moyer, Mary Pat
AU - De Plaen, Isabelle G.
AU - Shealy, David J.
AU - Yang, Guang Yu
AU - Barrett, Terrence A.
N1 - Funding Information:
through the National Cancer Institute (T32 CA080621, to support E.M.B.), and an Institutional Development Award from the National Institute of General Medical Sciences, National Institutes of Health (8 P20GM103527-05, to support tissue processing). Imaging work was also performed at the Northwestern Cell Imaging Facility, supported by National Cancer Institute Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center.
Funding Information:
This work was supported by a Veterans Affairs Merit Award (I01CX001353-0141 to T.A.B.), the National Institutes of Health (Grants R01AI061701 and R01DK-095662 to T.A.B.), the Training Program in Oncogenesis and Developmental Biology through the National Cancer Institute (T32 CA080621, to support E.M.B.), and an Institutional Development Award from the National Institute of General Medical Sciences, National Institutes of Health (8 P20GM103527-05, to support tissue processing). Imaging work was also performed at the Northwestern Cell Imaging Facility, supported by National Cancer Institute Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center
Funding Information:
This work was supported by a Veterans Affairs Merit Award (I01CX001353-0141 to T.A.B.), the National Institutes of Health (Grants R01AI061701 and R01DK-095662 to T.A.B.), the Training Program in Oncogenesis and Developmental Biology
Publisher Copyright:
Copyright © 2017 by The American Association of Immunologists, Inc.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - 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/ b-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/b-catenin signaling correlates with inflammation status. TNF-deficient (Tnf2/2) 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?Tnfr1/22/2 BM chimera mice with chronic dextran sodium sulfate colitis exhibited delayed ulcer healing, more mucosal inflammation, and impaired Wnt/b-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/b-catenin target gene expression in murine enteroids and colonoid cultures and TNF-induced b-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/b-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.
AB - 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/ b-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/b-catenin signaling correlates with inflammation status. TNF-deficient (Tnf2/2) 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?Tnfr1/22/2 BM chimera mice with chronic dextran sodium sulfate colitis exhibited delayed ulcer healing, more mucosal inflammation, and impaired Wnt/b-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/b-catenin target gene expression in murine enteroids and colonoid cultures and TNF-induced b-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/b-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.
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U2 - 10.4049/jimmunol.1601066
DO - 10.4049/jimmunol.1601066
M3 - Article
C2 - 28747340
AN - SCOPUS:85026873038
SN - 0022-1767
VL - 199
SP - 1886
EP - 1897
JO - Journal of Immunology
JF - Journal of Immunology
IS - 5
ER -
