{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T02:24:30Z","timestamp":1787797470358,"version":"build-2784847793"},"reference-count":110,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T00:00:00Z","timestamp":1674432000000},"content-version":"vor","delay-in-days":3827,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Japan National Center for Global Health and Medicine","award":["21-110"],"award-info":[{"award-number":["21-110"]}]},{"name":"The Japan National Center for Global Health and Medicine","award":["22-205"],"award-info":[{"award-number":["22-205"]}]},{"name":"Ministry of Health, Labor and Welfare of Japan"},{"name":"Biogen Idec, Inc"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Review on the TWEAK\/Fn14 pathway\u02c8s emerging role in inflammatory diseases, with focus on IBD, and its interaction with other pathways to influence pathological processes.<\/jats:p>\n                  <jats:p>The TWEAK\/Fn14 pathway is a ligand\/receptor pair of the TNFSF that has emerged as a prominent player in normal and pathological tissue remodeling. TWEAK\/Fn14 pathway activation drives many processes relevant to autoimmune and inflammatory diseases. IBDs, including CD and UC, are chronic, relapsing inflammatory diseases of the GI tract. These diseases differ in their clinical, macroscopic, and histopathological presentation; however, pathological processes that prominently contribute, more or less in each case, include breakdown of the mucosal epithelial barrier, chronic inflammation, and tissue remodeling with fibrosis. TWEAK may promote the pathogenesis of IBD by signaling through Fn14, which can be up-regulated on IECs, thereby contributing to breakdown of the mucosal barrier; the induction of IEC-derived mediators that promote chronic inflammation and shape gut immunity against commensal flora; and delayed healing and fibrosis. TWEAK may also exert its action on endothelial and stromal cell types, including smooth muscle cells and fibroblasts, to promote chronic inflammation, dysregulated tissue repair, and fibrosis. Here, we review the data supporting an emerging role of the TWEAK\/Fn14 pathway in autoimmune and inflammatory diseases, with a particular focus on IBD, and discuss how it interplays with other prominent pathways, including IL-13, TNF-\u03b1, and TGF-\u03b2, to aggravate and perpetuate the pathological processes underlying IBD.<\/jats:p>","DOI":"10.1189\/jlb.0112042","type":"journal-article","created":{"date-parts":[[2012,6,6]],"date-time":"2012-06-06T23:06:00Z","timestamp":1339023960000},"page":"265-279","source":"Crossref","is-referenced-by-count":58,"title":["The TWEAK\/Fn14 pathway as an aggravating and perpetuating factor in inflammatory diseases; focus on inflammatory bowel diseases"],"prefix":"10.1093","volume":"92","author":[{"given":"Taeko","family":"Dohi","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda C","family":"Burkly","sequence":"additional","affiliation":[{"name":"Department of Immunology, Biogen Idec , Cambridge, Massachusetts,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,8,1]]},"reference":[{"key":"2026041420270632400_jlb0265-cit-b1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/j.1600-065X.2011.01054.x","article-title":"TWEAK\/Fn14 pathway: an immunological switch for shaping tissue responses","volume":"244","author":"Burkly","year":"2011","journal-title":"Immunol. Rev."},{"key":"2026041420270632400_jlb0265-cit-b2","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/978-1-4419-6612-4_32","article-title":"The TWEAK\/Fn14 pathway in tissue remodeling: for better or for worse","volume":"691","author":"Burkly","year":"2011","journal-title":"Adv. Exp. Med. Biol."},{"key":"2026041420270632400_jlb0265-cit-b3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cyto.2007.09.007","article-title":"TWEAKing tissue remodeling by a multifunctional cytokine: role of TWEAK\/Fn14 pathway in health and disease","volume":"40","author":"Burkly","year":"2007","journal-title":"Cytokine"},{"key":"2026041420270632400_jlb0265-cit-b4","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/ki.2011.180","article-title":"TWEAK, a multifunctional cytokine in kidney injury","volume":"80","author":"Sanz","year":"2011","journal-title":"Kidney Int."},{"key":"2026041420270632400_jlb0265-cit-b5","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s12035-007-0024-z","article-title":"TWEAK and the central nervous system","volume":"35","author":"Yepes","year":"2007","journal-title":"Mol. Neurobiol."},{"key":"2026041420270632400_jlb0265-cit-b6","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1189\/jlb.0308165","article-title":"No end in site: TWEAK\/Fn14 activation and autoimmunity associated- end-organ pathologies","volume":"84","author":"Zheng","year":"2008","journal-title":"J. Leukoc. Biol."},{"key":"2026041420270632400_jlb0265-cit-b7","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/400_2008_18","article-title":"Therapeutic targeting of TWEAK\/Fnl4 in cancer: exploiting the intrinsic tumor cell killing capacity of the pathway","volume":"49","author":"Michaelson","year":"2009","journal-title":"Results Probl. Cell Differ."},{"key":"2026041420270632400_jlb0265-cit-b8","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nrd2488","article-title":"The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting","volume":"7","author":"Winkles","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"2026041420270632400_jlb0265-cit-b9","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/icb.2009.113","article-title":"Epithelium: the interplay between innate and Th2 immunity","volume":"88","author":"Bulek","year":"2010","journal-title":"Immunol. Cell Biol."},{"key":"2026041420270632400_jlb0265-cit-b10","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1111\/j.1600-065X.2008.00713.x","article-title":"Welcome to the neighborhood: epithelial cell-derived cytokines license innate and adaptive immune responses at mucosal sites","volume":"226","author":"Saenz","year":"2008","journal-title":"Immunol. Rev."},{"key":"2026041420270632400_jlb0265-cit-b11","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1016\/S0016-5085(03)00403-7","article-title":"Intestinal myofibroblasts in innate immune responses of the intestine","volume":"124","author":"Otte","year":"2003","journal-title":"Gastroenterology"},{"key":"2026041420270632400_jlb0265-cit-b12","doi-asserted-by":"crossref","first-page":"G684","DOI":"10.1152\/ajpgi.00474.2010","article-title":"Intestinal myofibroblasts: targets for stem cell therapy","volume":"300","author":"Mifflin","year":"2011","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"2026041420270632400_jlb0265-cit-b13","doi-asserted-by":"crossref","first-page":"32401","DOI":"10.1074\/jbc.272.51.32401","article-title":"TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis","volume":"272","author":"Chicheportiche","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2026041420270632400_jlb0265-cit-b14","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/j.cell.2005.09.022","article-title":"TWEAK attenuates the transition from innate to adaptive immunity","volume":"123","author":"Maecker","year":"2005","journal-title":"Cell"},{"key":"2026041420270632400_jlb0265-cit-b15","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/S0165-5728(02)00368-5","article-title":"TWEAK is expressed by glial cells, induces astrocyte proliferation and increases EAE severity","volume":"133","author":"Desplat-Jego","year":"2002","journal-title":"J. Neuroimmunol."},{"key":"2026041420270632400_jlb0265-cit-b16","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1161\/01.ATV.0000062883.93715.37","article-title":"TWEAK is an endothelial cell growth and chemotactic factor that also potentiates FGF-2 and VEGF-A mitogenic activity","volume":"23","author":"Donohue","year":"2003","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2026041420270632400_jlb0265-cit-b17","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1038\/sj.ki.5001866","article-title":"Cytokine cooperation in renal tubular cell injury: the role of TWEAK","volume":"70","author":"Justo","year":"2006","journal-title":"Kidney Int."},{"key":"2026041420270632400_jlb0265-cit-b18","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1053\/j.gastro.2008.11.017","article-title":"TWEAK\/Fn14 pathway: a nonredundant role in intestinal damage in mice through a TWEAK\/intestinal epithelial cell axis","volume":"136","author":"Dohi","year":"2009","journal-title":"Gastroenterology"},{"key":"2026041420270632400_jlb0265-cit-b19","first-page":"87","article-title":"Functional expression of TWEAK in human colonic adenocarcinoma cells","volume":"26","author":"Kawakita","year":"2005","journal-title":"Int. J. Oncol."},{"key":"2026041420270632400_jlb0265-cit-b20","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1084\/jem.192.9.1373","article-title":"Involvement of TWEAK in interferon \u03b3-stimulated monocyte cytotoxicity","volume":"192","author":"Nakayama","year":"2000","journal-title":"J. Exp. Med."},{"key":"2026041420270632400_jlb0265-cit-b21","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1084\/jem.20011956","article-title":"The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease","volume":"195","author":"Neurath","year":"2002","journal-title":"J. Exp. Med."},{"key":"2026041420270632400_jlb0265-cit-b22","doi-asserted-by":"crossref","first-page":"7234","DOI":"10.4049\/jimmunol.165.12.7234","article-title":"Up-regulation of the IL-12 receptor \u03b2 2 chain in Crohn's disease","volume":"165","author":"Parrello","year":"2000","journal-title":"J. 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Biol."},{"key":"2026041420270632400_jlb0265-cit-b27","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1053\/j.gastro.2011.08.040","article-title":"Interleukin-13 damages intestinal mucosa via TWEAK and Fn14 in mice-a pathway associated with ulcerative colitis","volume":"141","author":"Kawashima","year":"2011","journal-title":"Gastroenterology"},{"key":"2026041420270632400_jlb0265-cit-b28","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.cyto.2008.12.001","article-title":"TNF-like weak inducer of apoptosis (TWEAK) induces inflammatory and proliferative effects in human kidney cells","volume":"46","author":"Gao","year":"2009","journal-title":"Cytokine"},{"key":"2026041420270632400_jlb0265-cit-b29","doi-asserted-by":"crossref","first-page":"3329","DOI":"10.1111\/j.1582-4934.2009.00766.x","article-title":"Tweak induces proliferation in renal tubular epithelium: a role in uninephrectomy-induced renal hyperplasia","volume":"13","author":"Sanz","year":"2009","journal-title":"J. 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Ther."},{"key":"2026041420270632400_jlb0265-cit-b54","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.4049\/jimmunol.0803357","article-title":"TNF-like weak inducer of apoptosis (TWEAK) activates proinflammatory signaling pathways and gene expression through the activation of TGF-\u03b2-activated kinase 1","volume":"182","author":"Kumar","year":"2009","journal-title":"J. Immunol."},{"key":"2026041420270632400_jlb0265-cit-b55","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1093\/cvr\/cvp360","article-title":"TWEAK is a positive regulator of cardiomyocyte proliferation","volume":"85","author":"Novoyatleva","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"2026041420270632400_jlb0265-cit-b56","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1359\/jbmr.090305","article-title":"Pro-inflammatory cytokines TNF-related weak inducer of apoptosis (TWEAK) and TNF\u03b1 induce the mitogen-activated protein kinase (MAPK)-dependent expression of sclerostin in human osteoblasts","volume":"24","author":"Vincent","year":"2009","journal-title":"J. Bone Miner. Res."},{"key":"2026041420270632400_jlb0265-cit-b57","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/400_2008_18","article-title":"Therapeutic targeting of TWEAK\/Fn14 in cancer: exploiting the intrinsic tumor cell killing capacity of the pathway","volume":"49","author":"Michaelson","year":"2009","journal-title":"Results Probl. Cell Differ."},{"key":"2026041420270632400_jlb0265-cit-b58","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1016\/j.neuroscience.2010.10.029","article-title":"Tumor necrosis factor-like weak inducer of apoptosis and fibroblast growth factor-inducible 14 mediate cerebral ischemia-induced poly(ADP-ribose) polymerase-1 activation and neuronal death","volume":"171","author":"Haile","year":"2010","journal-title":"Neuroscience"},{"key":"2026041420270632400_jlb0265-cit-b59","doi-asserted-by":"crossref","first-page":"362","DOI":"10.4161\/mabs.3.4.16090","article-title":"Development of an Fn14 agonistic antibody as an anti-tumor agent","volume":"3","author":"Michaelson","year":"2011","journal-title":"MAbs"},{"key":"2026041420270632400_jlb0265-cit-b60","doi-asserted-by":"crossref","first-page":"734","DOI":"10.4049\/jimmunol.168.2.734","article-title":"Multiple pathways of TWEAK-induced cell death","volume":"168","author":"Nakayama","year":"2002","journal-title":"J. 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