{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:47:40Z","timestamp":1787014060961,"version":"build-2736575974"},"reference-count":38,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Interleukin 6 (IL\u20106) has previously been identified as playing a role in ulcerative colitis (UC) by activating the signal\u2010transducing element gp130 through ligation of either the membrane\u2010bound or soluble IL\u20106 receptor (termed classic and trans\u2010signaling respectively). It has been proposed that selective inhibition of trans\u2010IL\u20106 signaling could ameliorate the deleterious, pro\u2010inflammatory effects of IL\u20106, while preserving the homeostatic activity of classic IL\u20106 signaling. We developed an\n                    <jats:italic>in silico<\/jats:italic>\n                    , mechanistic model of UC in two stages to compare the biological effects that result from inhibition of classic and trans\u2010IL\u20106 signaling. In the first stage, we developed a limited\u2010scope model of IL\u20106 signaling to establish the quantitative properties of classic and trans\u2010signaling pathways on a short timescale following stimulation with IL\u20106. The model included both a pan\u2010inhibitor of IL\u20106 classic and trans\u2010signaling and a soluble gp130\u2010Fc that selectively inhibited trans\u2010signaling. In the second stage, we developed a multi\u2010scale model of UC to study the pharmacodynamic effects of cytokine signaling inhibition and optimize treatment regimens. Across three virtual experiments, both selective and global suppression of IL\u20106 signaling were associated with a transition away from an inflammatory state in patients with moderate to severe inflammatory activity. In our multi\u2010scale model, we identified a dose\u2013response relationship between selective inhibition of trans\u2010IL\u20106 signaling and tissue regeneration. Moreover, selective inhibition of trans\u2010IL\u20106 signaling effectively suppressed inflammation and induced faster gut tissue healing than global IL\u20106 suppression. These findings suggest that global suppression of IL\u20106 signaling could negatively affect IL\u20106\u2010induced regeneration activity, whereas this effect is less likely for selective inhibition.\n                  <\/jats:p>","DOI":"10.1111\/cts.70366","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T06:57:01Z","timestamp":1758265021000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Multi\u2010Scale Mechanistic Model of Ulcerative Colitis to Investigate the Effects of Selective Suppression of\n                    <scp>IL<\/scp>\n                    \u20106 Trans\u2010Signaling"],"prefix":"10.1111","volume":"18","author":[{"given":"Ola","family":"Sternebring","sequence":"first","affiliation":[{"name":"Ferring Pharmaceuticals, Global Research &amp; Medical  Kastrup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikhil","family":"Patidar","sequence":"additional","affiliation":[{"name":"PricewaterhouseCoopers Advisory Services LLC  USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjun","family":"Ravi","sequence":"additional","affiliation":[{"name":"Ferring Pharmaceuticals, Global Research &amp; Medical  Kastrup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Carcillo","sequence":"additional","affiliation":[{"name":"PricewaterhouseCoopers Advisory Services LLC  USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aymeric","family":"Rivollier","sequence":"additional","affiliation":[{"name":"Ferring Pharmaceuticals, Global Research &amp; Medical  Kastrup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyu","family":"Wang","sequence":"additional","affiliation":[{"name":"PricewaterhouseCoopers  Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3816-7418","authenticated-orcid":false,"given":"Sai Phanindra","family":"Venkatapurapu","sequence":"additional","affiliation":[{"name":"PricewaterhouseCoopers Advisory Services LLC  USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo","family":"Behar","sequence":"additional","affiliation":[{"name":"PricewaterhouseCoopers Advisory Services LLC  USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Read","sequence":"additional","affiliation":[{"name":"Ferring Pharmaceuticals, Global Research &amp; Medical  Kastrup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rose","family":"Szabady","sequence":"additional","affiliation":[{"name":"Ferring Pharmaceuticals, Global Research &amp; Medical  Kastrup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f8rgen","family":"S\u00f8rensen","sequence":"additional","affiliation":[{"name":"PricewaterhouseCoopers  Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"D'Alessandro","sequence":"additional","affiliation":[{"name":"PricewaterhouseCoopers Advisory Services LLC  USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4227-7687","authenticated-orcid":false,"given":"Philippe","family":"Pinton","sequence":"additional","affiliation":[{"name":"Ferring Pharmaceuticals, Global Research &amp; Medical  Kastrup 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