{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T14:46:21Z","timestamp":1789569981519,"version":"build-2803163510"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T00:00:00Z","timestamp":1655078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018286","name":"Dutch Arthritis Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018286","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009425","name":"Landsteiner Foundation for Blood Transfusion Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009425","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Endothelial cells (ECs) are important contributors to inflammation in immune-mediated inflammatory diseases (IMIDs). In this study, we examined whether CD4\n                    <jats:sup>+<\/jats:sup>\n                    memory T (T\n                    <jats:sub>m<\/jats:sub>\n                    ) cells can drive EC inflammatory responses. Human T\n                    <jats:sub>m<\/jats:sub>\n                    cells produced ligands that induced inflammatory responses in human umbilical vein EC as exemplified by increased expression of inflammatory mediators including chemokines and adhesion molecules. NF-\u03baB, a key regulator of EC activation, was induced by T\n                    <jats:sub>m<\/jats:sub>\n                    cell ligands. We dissected the relative contribution of canonical and non-canonical NF-\u03baB signaling to T\n                    <jats:sub>m<\/jats:sub>\n                    induced EC responses using pharmacological small molecule inhibitors of IKK\u03b2 (iIKK\u03b2) or NF-\u03baB inducing kinase (iNIK). RNA sequencing revealed substantial overlap in IKK\u03b2 and NIK regulated genes (n=549) that were involved in inflammatory and immune responses, including cytokines (IL-1\u03b2, IL-6, GM-CSF) and chemokines (CXCL5, CXCL1). NIK regulated genes were more restricted, as 332 genes were uniquely affected by iNIK versus 749 genes by iIKK\u03b2, the latter including genes involved in metabolism, proliferation and leukocyte adhesion (VCAM-1, ICAM-1). The functional importance of NIK and IKK\u03b2 in EC activation was confirmed by transendothelial migration assays with neutrophils, demonstrating stronger inhibitory effects of iIKK\u03b2 compared to iNIK. Importantly, iIKK\u03b2 \u2013 and to some extent iNIK - potentiated the effects of currently employed therapies for IMIDs, like JAK inhibitors and anti-IL-17 antibodies, on EC inflammatory responses. These data demonstrate that inhibition of NF-\u03baB signaling results in modulation of T\n                    <jats:sub>m<\/jats:sub>\n                    cell-induced EC responses and highlight the potential of small molecule NF-\u03baB inhibitors as a novel treatment strategy to target EC inflammatory responses in IMIDs.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.860327","type":"journal-article","created":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T08:56:22Z","timestamp":1655110582000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Differential Contribution of NF-\u03baB Signaling Pathways to CD4+ Memory T Cell Induced Activation of Endothelial Cells"],"prefix":"10.3389","volume":"13","author":[{"given":"Kim C. M.","family":"Jeucken","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte C. 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