{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T13:18:50Z","timestamp":1770297530382,"version":"3.49.0"},"reference-count":22,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2012,4,26]],"date-time":"2012-04-26T00:00:00Z","timestamp":1335398400000},"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":[[2012,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Pattern\u2010recognition receptors (PRRs), such as Toll\u2010like receptors (TLRs) and nucleotide\u2010binding oligomerization domain\u2013containing protein 2 (NOD\u20102), have been shown to contribute to the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to analyze the expression, regulation, and function of the PRR NOD\u20101 in RA synovial fibroblasts (RASFs), and to examine its interaction with other PRRs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Expression of NOD\u20101 was analyzed by immunohistochemistry in synovial tissue from RA patients, psoriatic arthritis patients, gout patients, and osteoarthritis (OA) patients. RASFs and human monocyte\u2010derived macrophages (HMDMs) were stimulated with <jats:sc>L<\/jats:sc>\u2010alanyl\u2010\u03b3\u2010<jats:sc>D<\/jats:sc>\u2010glutamyl\u2010meso\u2010diaminopimelic acid, palmitoyl\u20103\u2010cysteine\u2010serine\u2010lysine\u20104, poly(I\u2010C), lipopolysaccharide, heat\u2010inactivated bacteria, tumor necrosis factor \u03b1 (TNF\u03b1), or interleukin\u20101\u03b2 (IL\u20101\u03b2). Expression levels of IL\u20106, CCL5, matrix metalloproteinases (MMPs), NODs, and TLRs were measured by real\u2010time reverse transcription\u2013polymerase chain reaction and\/or enzyme\u2010linked immunosorbent assay. NOD\u20101 and NOD\u20102 were silenced with target\u2010specific small interfering RNA. Phosphorylation of IL\u20101 receptor\u2013associated kinase 1 (IRAK\u20101) was measured by Western blotting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Expression of NOD\u20101 protein was significantly increased in RA synovium compared to OA synovium. The basal expression of NOD\u20101 was similar in RASFs, OASFs, healthy control peripheral blood mononuclear cells, and healthy control HMDMs. Stimulation of RASFs with TLR\u20103 up\u2010regulated the expression of NOD\u20101. Expression of IL\u20106, CCL5, MMPs, TLR\u20102, and NOD\u20102 was significantly up\u2010regulated in RASFs by stimulation with the NOD\u20101 ligand. A synergistic effect on IL\u20106 production was observed in cells stimulated with NOD\u20101 and TLR\u20102 ligands or NOD\u20101 and TLR\u20104 ligands. Silencing of NOD\u20101, but not NOD\u20102, decreased the levels of IL\u20106 in RASFs after stimulation with TLR\u20102 and IL\u20101\u03b2, and blocked the phosphorylation of IRAK\u20101.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>NOD\u20101 is strongly expressed in different cell types in the synovial tissue of patients with RA. These results indicate that NOD\u20101, either alone or interacting with other inflammatory mediators, can play an important role in the chronic and destructive inflammation of the joints in RA.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.34318","type":"journal-article","created":{"date-parts":[[2011,12,5]],"date-time":"2011-12-05T18:36:24Z","timestamp":1323110184000},"page":"1329-1337","source":"Crossref","is-referenced-by-count":31,"title":["The pattern\u2010recognition receptor nucleotide\u2010binding oligomerization domain\u2013containing protein 1 promotes production of inflammatory mediators in rheumatoid arthritis synovial fibroblasts"],"prefix":"10.1002","volume":"64","author":[{"given":"Kazuhiro","family":"Yokota","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Miyazaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hossein","family":"Hemmatazad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renate E.","family":"Gay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Kolling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ursula","family":"Fearon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiromichi","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihide","family":"Mimura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steffen","family":"Gay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"Ospelt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,4,26]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.20984"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/9554"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1747"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2008.00734.x"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.21273"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.24140"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.24226"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304355200"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200526286"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni945"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1131"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2006.00686.x"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.1.484"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200526296"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi135"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi087"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780310302"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0710445105"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(02)02714-6"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200003)43:3<593::AID-ANR16>3.0.CO;2-1"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M502820200"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1184004"}],"container-title":["Arthritis &amp; 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