{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:05:42Z","timestamp":1790827542000,"version":"4.1.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T00:00:00Z","timestamp":1697673600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100005564","name":"Gilead Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Janus kinase [JAK] inhibitors [JAKinibs] are effective small molecule therapies for treating Crohn\u2019s disease [CD] and ulcerative colitis [UC], collectively known as inflammatory bowel disease [IBD]. By preventing JAKs from phosphorylating signal transducer and activator of transcription proteins, JAKinibs disrupt cytokine signalling pathways that promote inflammation. Despite considerable overlap in the JAKs they target, first- and second-generation JAKinibs display different clinical efficacies in CD and UC.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted a comparative phosflow study of four JAKinibs [filgotinib, upadacitinib, tofacitinib, and deucravacitinib] to observe subtle mechanistic differences that may dictate their clinical behaviour. Resected mesenteric lymph node [MLN] cells from 19 patients [9 CD, 10 UC] were analysed by flow cytometry in the presence or absence of different cytokine stimuli and titrated JAKinibs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We found a higher potency of the JAK 1\/3-preferential inhibitor, tofacitinib, for JAK 3-dependent cytokine signalling pathways in comparison to filgotinib, but a higher potency of the JAK 1-preferential inhibitors, filgotinib and upadacitinib, for JAK 3-independent cytokine signalling pathways. Deucravacitinib, a TYK2-preferential inhibitor, demonstrated a much narrower selectivity by inhibiting only IL-10 and IFN-\u03b2 pathways, albeit more potently than the other JAKinibs. Additionally, we found some differences in the sensitivity of immune cells from CD versus UC, and patients with versus without a CD-associated NOD2 polymorphism, to phosphorylate signal transducer and activator of transcriptions in response to specific cytokine stimulation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Despite their similarities, differences exist in the relative potencies of different JAKinibs against distinct cytokine families, to explain their clinical efficacy.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ecco-jcc\/jjad173","type":"journal-article","created":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T11:39:39Z","timestamp":1697715579000},"page":"628-637","source":"Crossref","is-referenced-by-count":16,"title":["Janus Kinase Inhibitors Differentially Inhibit Specific Cytokine Signals in the Mesenteric Lymph Node Cells of Inflammatory Bowel Disease Patients"],"prefix":"10.1093","volume":"18","author":[{"given":"Duncan C","family":"Hindmarch","sequence":"first","affiliation":[{"name":"Benaroya Research Institute, Translation Research Division , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofya","family":"Malashanka","sequence":"additional","affiliation":[{"name":"Virginia Mason Medical Center, Gastroenterology Division, Internal Medicine Department , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna M","family":"Shows","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute, Translation Research Division , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid S","family":"Clarke","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Research Division , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8961-3660","authenticated-orcid":false,"given":"James D","family":"Lord","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute, Translation Research Division , Seattle, WA , USA"},{"name":"Virginia Mason Medical Center, Gastroenterology Division, Internal Medicine Department , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,10,19]]},"reference":[{"key":"2024042313301549800_CIT0001","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1056\/NEJMoa1606910","article-title":"Tofacitinib as induction and maintenance therapy for ulcerative colitis","volume":"376","author":"Sandborn","year":"2017","journal-title":"N Engl J Med"},{"key":"2024042313301549800_CIT0002","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/S0140-6736(16)32537-5","article-title":"Clinical remission 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