{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:37:57Z","timestamp":1790048277090,"version":"4.0.1"},"reference-count":29,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2016,12,12]],"date-time":"2016-12-12T00:00:00Z","timestamp":1481500800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunology"],"published-print":{"date-parts":[[2017,3]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Refractory coeliac disease (<jats:styled-content style=\"fixed-case\">RCD<\/jats:styled-content>) is a form of coeliac disease (<jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>) resistant to gluten\u2010free diet and associated with elevated risk of complications. Many effector cytokines over\u2010produced in the gut of patients with <jats:styled-content style=\"fixed-case\">RCD<\/jats:styled-content> are supposed to amplify the tissue\u2010destructive immune response, but it remains unclear if the <jats:styled-content style=\"fixed-case\">RCD<\/jats:styled-content>\u2010associated mucosal inflammation is sustained by defects in counter\u2010regulatory mechanisms. The aim of the present study was to determine whether <jats:styled-content style=\"fixed-case\">RCD<\/jats:styled-content>\u2010related inflammation is marked by high Smad7, an intracellular inhibitor of transforming growth factor\u2010<jats:italic>\u03b2<\/jats:italic><jats:sub>1<\/jats:sub> (<jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u2010<jats:italic>\u03b2<\/jats:italic><jats:sub>1<\/jats:sub>) activity. Smad7 was evaluated in duodenal biopsy samples of patients with <jats:styled-content style=\"fixed-case\">RCD<\/jats:styled-content>, patients with active <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>, patients with inactive <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content> and healthy controls by Western blotting, immunohistochemistry and real\u2010time <jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content>. In the same samples, <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u2010<jats:italic>\u03b2<\/jats:italic><jats:sub>1<\/jats:sub> and phosphorylated (p)\u2010Smad2\/3 were evaluated by <jats:styled-content style=\"fixed-case\">ELISA<\/jats:styled-content> and immunohistochemistry, respectively. Pro\u2010inflammatory cytokine expression was evaluated in <jats:styled-content style=\"fixed-case\">RCD<\/jats:styled-content> samples cultured with Smad7 sense or antisense oligonucleotide. Smad7 protein, but not <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>, expression was increased in <jats:styled-content style=\"fixed-case\">RCD<\/jats:styled-content> compared with active and inactive <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content> patients and healthy controls and this was associated with defective <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u2010<jats:italic>\u03b2<\/jats:italic><jats:sub>1<\/jats:sub> signalling, as marked by diminished p\u2010Smad2\/3 expression. <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u2010<jats:italic>\u03b2<\/jats:italic><jats:sub>1<\/jats:sub> protein content did not differ among groups. Knockdown of Smad7 in <jats:styled-content style=\"fixed-case\">RCD<\/jats:styled-content> biopsy samples reduced interleukin\u20106 and tumour necrosis factor\u2010<jats:italic>\u03b1<\/jats:italic> expression. In conclusion, in <jats:styled-content style=\"fixed-case\">RCD<\/jats:styled-content>, high Smad7 associates with defective <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u2010<jats:italic>\u03b2<\/jats:italic><jats:sub>1<\/jats:sub> signalling and sustains inflammatory cytokine production. These results indicate a novel mechanism by which the mucosal cytokine response is amplified in <jats:styled-content style=\"fixed-case\">RCD<\/jats:styled-content> and suggest that targeting Smad7 can be therapeutically useful in <jats:styled-content style=\"fixed-case\">RCD<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/imm.12690","type":"journal-article","created":{"date-parts":[[2016,11,16]],"date-time":"2016-11-16T16:42:43Z","timestamp":1479314563000},"page":"356-363","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["High Smad7 sustains inflammatory cytokine response in refractory coeliac disease"],"prefix":"10.1111","volume":"150","author":[{"given":"Silvia","family":"Sedda","sequence":"first","affiliation":[{"name":"Department of Systems Medicine University of Rome \u201cTor Vergata\u201d Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"De Simone","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine University of Rome \u201cTor Vergata\u201d Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Marafini","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine University of Rome \u201cTor Vergata\u201d Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerolamo","family":"Bevivino","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine University of Rome \u201cTor Vergata\u201d Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Izzo","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine University of Rome \u201cTor Vergata\u201d Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omero Alessandro","family":"Paoluzi","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine 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