{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T16:25:02Z","timestamp":1793377502880,"version":"4.5.0"},"reference-count":50,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2013,3,28]],"date-time":"2013-03-28T00:00:00Z","timestamp":1364428800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2013,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The nonresolving character of synovial inflammation in rheumatoid arthritis (RA) is a conundrum. To identify the contribution of fibroblast\u2010like synoviocytes (FLS) to the perpetuation of synovitis, we investigated the molecular mechanisms that govern the tumor necrosis factor \u03b1 (TNF\u03b1)\u2013driven inflammatory program in human FLS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>FLS obtained from the synovial tissues of patients with RA or osteoarthritis were stimulated with TNF\u03b1 and assayed for gene expression and cytokine production by real\u2010time quantitative reverse transcription\u2013polymerase chain reaction analysis and enzyme\u2010linked immunosorbent assay. NF\u2010\u03baB signaling was evaluated by Western blotting. Histone acetylation, chromatin accessibility, and NF\u2010\u03baB p65 and RNA polymerase II (Pol II) occupancy at the interleukin\u20106 (IL\u20106) promoter were measured by chromatin immunoprecipitation and restriction enzyme accessibility assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In FLS, TNF\u03b1 induced prolonged transcription of messenger RNA (mRNA) for IL\u20106 and progressive accumulation of IL\u20106 protein over 4 days. Similarly, induction of mRNA for CXCL8\/IL\u20108, CCL5\/RANTES, matrix metalloproteinase 1 (MMP\u20101), and MMP\u20103 after TNF\u03b1 stimulation was sustained for several days. This contrasted with the macrophage response to TNF\u03b1, which characteristically involved a transient increase in the expression of proinflammatory genes. In FLS, TNF\u03b1 induced prolonged activation of NF\u2010\u03baB signaling and sustained transcriptional activity, as indicated by increased histone acetylation, chromatin accessibility, and p65 and Pol II occupancy at the IL\u20106 promoter. Furthermore, FLS expressed low levels of the feedback inhibitors A20\u2010binding inhibitor of NF\u2010\u03baB activation 3 (ABIN\u20103), IL\u20101 receptor\u2013associated kinase M (IRAK\u2010M), suppressor of cytokine signaling 3 (SOCS\u20103), and activating transcription factor 3 (ATF\u20103), which terminate inflammatory responses in macrophages.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>TNF\u03b1 signaling is not effectively terminated in FLS, which leads to an uncontrolled inflammatory response. The results suggest that prolonged and sustained inflammatory responses by FLS in response to synovial TNF\u03b1 contribute to the persistence of synovial inflammation in RA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.37853","type":"journal-article","created":{"date-parts":[[2013,1,17]],"date-time":"2013-01-17T15:55:00Z","timestamp":1358438100000},"page":"928-938","source":"Crossref","is-referenced-by-count":156,"title":["Tumor Necrosis Factor \u03b1 Induces Sustained Signaling and a Prolonged and Unremitting Inflammatory Response in Rheumatoid Arthritis Synovial Fibroblasts"],"prefix":"10.1002","volume":"65","author":[{"given":"Angela","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina","family":"Grigoriev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung\u2010Hyun","family":"Park\u2010Min","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Ho","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lionel B.","family":"Ivashkiv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George 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