{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T09:41:31Z","timestamp":1793353291144,"version":"4.5.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2012,3,2]],"date-time":"2012-03-02T00:00:00Z","timestamp":1330646400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,3,2]]},"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>Transglutaminase 2 (TG2) is expressed ubiquitously, has multiple physiological functions and has also been associated with inflammatory diseases, neurodegenerative disorders, autoimmunity and cancer. In particular, TG2 is expressed in small intestine mucosa where it is up-regulated in active coeliac disease (CD). The aim of this work was to investigate the induction of TG2 expression by proinflammatory cytokines [interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)-\u03b1, interferon (IFN)-\u03b3 and IL-15] and the signalling pathways involved, in human epithelial and monocytic cells and in intestinal tissue from controls and untreated CD patients. Here we report that IFN-\u03b3 was the most potent inducer of TG2 expression in the small intestinal mucosa and in four [Caco-2, HT-29, Calu-6 and human acute monocytic leukaemia cell line (THP-1)] of five cell lines tested. The combination of TNF-\u03b1 and IFN-\u03b3 produced a strong synergistic effect. The use of selective inhibitors of signalling pathways revealed that induction of TG2 by IFN-\u03b3 was mediated by phosphoinositide 3-kinase (PI3K), while c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) were required for TNF-\u03b1 activation. Quantitative polymerase chain reaction (PCR), flow cytometry and Western blot analysis showed that TG2 expression was blocked completely when stimulation by either TNF-\u03b1 or IFN-\u03b3 was performed in the presence of nuclear factor (NF)-\u03baB inhibitors (sulphasalazine and BAY-117082). TG2 was up-regulated substantially by TNF-\u03b1 and IFN-\u03b3 in intestinal mucosa in untreated CD compared with controls. This study shows that IFN-\u03b3, a dominant cytokine in intestinal mucosa in active CD, is the most potent inducer of TG2, and synergism with TNF-\u03b1 may contribute to exacerbate the pathogenic mechanism of CD. Selective inhibition of signalling pathways may be of therapeutic benefit.<\/jats:p>","DOI":"10.1111\/j.1365-2249.2011.04545.x","type":"journal-article","created":{"date-parts":[[2011,12,9]],"date-time":"2011-12-09T09:01:50Z","timestamp":1323421310000},"page":"95-104","source":"Crossref","is-referenced-by-count":46,"title":["Transglutaminase 2 expression is enhanced synergistically by interferon-\u03b3 and tumour necrosis factor-\u03b1 in human small intestine"],"prefix":"10.1093","volume":"168","author":[{"given":"M","family":"Bayardo","sequence":"first","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en el Sistema Inmune \u2013 LISIN, Departamento de Ciencias Biol\u00f3gicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Punzi","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en el Sistema Inmune \u2013 LISIN, Departamento de Ciencias Biol\u00f3gicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Bondar","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en el Sistema Inmune \u2013 LISIN, Departamento de Ciencias Biol\u00f3gicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Chopita","sequence":"additional","affiliation":[{"name":"Servicio de Gastroenterolog\u00eda, Hospital Interzonal de Agudos \u2018Jos\u00e9 de San Martin\u2019, La Plata, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Chirdo","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en el Sistema Inmune \u2013 LISIN, Departamento de Ciencias Biol\u00f3gicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,3,2]]},"reference":[{"key":"2021122708380308700_b1","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/nrm1014","article-title":"Transglutaminases: crosslinking enzymes with pleiotropic functions","volume":"4","author":"Lorand","year":"2003","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2021122708380308700_b2","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/S0968-0004(02)02182-5","article-title":"Transglutaminase 2: an enigmatic enzyme with diverse functions","volume":"27","author":"Fesus","year":"2002","journal-title":"Trends Biochem Sci"},{"key":"2021122708380308700_b3","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1007\/s00726-010-0500-z","article-title":"Transglutaminase 2: a multi-functional protein in multiple subcellular compartments","volume":"39","author":"Park","year":"2010","journal-title":"Amino 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