{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T03:41:06Z","timestamp":1789184466244,"version":"build-2803163510"},"reference-count":33,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2016,5,26]],"date-time":"2016-05-26T00:00:00Z","timestamp":1464220800000},"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; Rheumatology"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate whether epigenetic changes can modulate monocytes to produce tissue inhibitor of metalloproteinases 1 (TIMP\u20101) via Fra\u20102 (an activator protein 1 [AP\u20101] family member), a novel downstream mediator that promotes fibrogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>AP\u20101 transcription factors and TIMP\u20101 expression were measured in monocytes from systemic sclerosis (SSc) patients and healthy controls. Involvement of Fra\u20102 in the regulation of TIMP\u20101 following treatment with Toll\u2010like receptor 8 (TLR\u20108) agonist was investigated using a luciferase activity assay and chromatin immunoprecipitation (ChIP) analysis. Expression of TIMP\u20101 and Fra\u20102 was determined in response to TLR\u20108 treatment and to different histone modifications, including 3\u2032\u2010deazaneplanocin (DZNep) and apicidin. Fibroblasts from healthy controls were cocultured with DZNep plus TLR\u20108\u2013treated healthy control monocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Up\u2010regulation of Fra\u20102 was detected in bleomycin\u2010challenged mice and in skin biopsy samples from SSc patients. Enhanced expression of Fra\u20102 and TIMP\u20101 was correlated in SSc monocytes (<jats:italic>P<\/jats:italic>\u2009=\u20090.021). The expression of Fra\u20101 was significantly reduced (<jats:italic>P<\/jats:italic>\u2009=\u20090.037) in SSc monocytes. Inhibiting AP\u20101 activity reduced TIMP\u20101 production in TLR\u20108\u2013stimulated monocytes from healthy controls and SSc patients. ChIP experiments revealed binding of Fra\u20102 to the TIMP\u20101 promoter. Stimulation with DZNep plus TLR\u20108 enhanced Fra\u20102 and TIMP\u20101 expression in healthy control monocytes, whereas TLR\u20108 plus apicidin repressed Fra\u20102 and TIMP\u20101 expression. Finally, healthy control monocytes treated with DZNep plus TLR\u20108 induced strong production of \u03b1\u2010smooth muscle actin in dermal fibroblasts, which was inhibited by TIMP\u20101\u2013blocking antibody.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data demonstrate a novel role of histone demethylation induced by DZNep on Fra\u20102\u2013mediated TIMP\u20101 production by monocytes in the presence of TLR\u20108 agonist. This consequently orchestrates the transdifferentiation of fibroblasts, a key event in the pathogenesis of SSc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39602","type":"journal-article","created":{"date-parts":[[2016,1,27]],"date-time":"2016-01-27T15:14:23Z","timestamp":1453907663000},"page":"1493-1504","source":"Crossref","is-referenced-by-count":46,"title":["Histone Demethylation and Toll\u2010like Receptor 8\u2013Dependent Cross\u2010Talk in Monocytes Promotes Transdifferentiation of Fibroblasts in Systemic Sclerosis Via Fra\u20102"],"prefix":"10.1002","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0961-6130","authenticated-orcid":false,"given":"Marzena","family":"Ciechomska","sequence":"first","affiliation":[{"name":"Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK, L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland, and National Institute of Geriatrics, Rheumatology, and Rehabilitation Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"O'Reilly","sequence":"additional","affiliation":[{"name":"Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK, and Durham University, School of Biological and Biomedical Sciences Durham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Przyborski","sequence":"additional","affiliation":[{"name":"Durham University, School of Biological and Biomedical Sciences Durham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Oakley","sequence":"additional","affiliation":[{"name":"Institute of Cellular Medicine, Newcastle University Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Bogunia\u2010Kubik","sequence":"additional","affiliation":[{"name":"Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, and Wroclaw Medical University Wroclaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob M.","family":"van Laar","sequence":"additional","affiliation":[{"name":"Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK, and University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,5,26]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31139"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2012.04.003"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00402.2004"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.3616"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3066"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-201958"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201010-1719OC"},{"key":"e_1_2_7_9_1","first-page":"232","article-title":"Effect of CsA bleomycin\u2010induced interstitial pulmonary disease in mice","volume":"28","author":"Ren Y","year":"2012","journal-title":"Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101840200"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510290333"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.33501"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-200940"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01414"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-201615"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.10.002"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0098176"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22759"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.24494"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100479"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22952"},{"key":"e_1_2_7_22_1","first-page":"202","article-title":"Scleroderma (systemic sclerosis): classification, subsets, and pathogenesis","volume":"15","author":"LeRoy EC","year":"1988","journal-title":"J Rheumatol"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02634257"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1756-185X.2009.01410.x"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.25056"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27647"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0041611"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2011.101"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24175"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2013.12.013"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0033508"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.8.59"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1933744100"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/gene.2014.44"}],"container-title":["Arthritis &amp; 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