{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:07:59Z","timestamp":1791198479024,"version":"4.1.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2017,9,1]],"date-time":"2017-09-01T00:00:00Z","timestamp":1504224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>TNF plays an integral role in inflammatory bowel disease (IBD), as evidenced by the dramatic therapeutic responses in Crohn\u2019s 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\/\u03b2-catenin\u2013mediated 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\/\u03b2-catenin signaling correlates with inflammation status. TNF-deficient (Tnf\u2212\/\u2212) 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\u2013derived cells and TNFR expression by radioresistant IECs. Wild-type\u2192Tnfr1\/2\u2212\/\u2212 BM chimera mice with chronic dextran sodium sulfate colitis exhibited delayed ulcer healing, more mucosal inflammation, and impaired Wnt\/\u03b2-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\/\u03b2-catenin target gene expression in murine enteroids and colonoid cultures and TNF-induced \u03b2-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\/\u03b2-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.<\/jats:p>","DOI":"10.4049\/jimmunol.1601066","type":"journal-article","created":{"date-parts":[[2017,7,27]],"date-time":"2017-07-27T00:25:35Z","timestamp":1501115135000},"page":"1886-1897","source":"Crossref","is-referenced-by-count":132,"title":["Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease"],"prefix":"10.1093","volume":"199","author":[{"given":"Emily M","family":"Bradford","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Northwestern University Feinberg School of Medicine , Chicago, IL 60611"},{"name":"Division of Gastroenterology, University of Kentucky , Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5448-339X","authenticated-orcid":false,"given":"Stacy H","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Northwestern University Feinberg School of Medicine , Chicago, IL 60611"},{"name":"Driskill Graduate Program in Life Sciences, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Northwestern University Feinberg School of Medicine , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay Pal","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Northwestern University Feinberg School of Medicine , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3025-5234","authenticated-orcid":false,"given":"Goo","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Northwestern University Feinberg School of Medicine , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Goretsky","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Northwestern University Feinberg School of Medicine , Chicago, IL 60611"},{"name":"Division of Gastroenterology, University of Kentucky , Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preetika","family":"Sinh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Northwestern University Feinberg School of Medicine , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Northwestern University Feinberg School of Medicine , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber L","family":"Cloud","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, University of Kentucky , Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8679-9711","authenticated-orcid":false,"given":"Elias","family":"Gounaris","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Northwestern University Feinberg School of Medicine , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vihang","family":"Patel","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, University of Kentucky , Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia F","family":"Lamping","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, University of Kentucky , Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan B","family":"Lynch","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, University of Kentucky , Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0297-8921","authenticated-orcid":false,"given":"Mary Pat","family":"Moyer","sequence":"additional","affiliation":[{"name":"INCELL Corporation , San Antonio, TX 78249"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle G","family":"De Plaen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Northwestern University Feinberg School of Medicine , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9591-976X","authenticated-orcid":false,"given":"David J","family":"Shealy","sequence":"additional","affiliation":[{"name":"Janssen Research & Development , Radnor, PA 19087"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang-Yu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Northwestern University Feinberg School of Medicine , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terrence A","family":"Barrett","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Ann & Robert H. 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