{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:36:50Z","timestamp":1790617010276,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2014,8,11]],"date-time":"2014-08-11T00:00:00Z","timestamp":1407715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","award":["HI09C1555"],"award-info":[{"award-number":["HI09C1555"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2009-0080087"],"award-info":[{"award-number":["2009-0080087"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2011-0020163"],"award-info":[{"award-number":["2011-0020163"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[2014,9]]},"abstract":"<jats:p>NFAT5 (nuclear factor of activated T cells), a well\u2010known osmoprotective factor, can be activated by isotonic stimuli such as Toll\u2010like receptor (TLR) triggering. However, it is unclear how NFAT5 discriminates between isotonic and hypertonic stimuli to produce different functional and molecular outcomes. Here, we identified a novel XO\u2013ROS\u2013p38 MAPK\u2013NFAT5 pathway (XO is xanthine oxidase, ROS is reactive oxygen species) that is activated in RAW 264.7 macrophages upon isotonic TLR stimulation. Unlike what is seen under hypertonic conditions, XO\u2010derived ROS were selectively required for the TLR\u2010induced NFAT5 activation and NFAT5 binding to the IL\u20106 promoter in RAW 264.7 macrophages under isotonic conditions. In mouse peritoneal macrophages and human macrophages, TLR ligation also induced NFAT5 activation, which was dependent on XO and p38 kinase. The involvement of XO in NFAT5 activation by TLR was confirmed in RAW 264.7 macrophages implanted in <jats:italic>BALB\/c<\/jats:italic> mice. Moreover, allopurinol, an XO inhibitor, suppressed arthritis severity and decreased the expression of NFAT5 and IL\u20106 in splenic macrophages in <jats:italic>C57BL\/6<\/jats:italic> mice. Collectively, these data support a novel function of the XO\u2013NFAT5 axis in macrophage activation and TLR\u2010induced arthritis, and suggest that XO inhibitor(s) could serve as a therapeutic agent for chronic inflammatory arthritis.<\/jats:p>","DOI":"10.1002\/eji.201343669","type":"journal-article","created":{"date-parts":[[2014,7,15]],"date-time":"2014-07-15T14:55:21Z","timestamp":1405436121000},"page":"2721-2736","source":"Crossref","is-referenced-by-count":43,"title":["The xanthine oxidase\u2013NFAT5 pathway regulates macrophage activation and TLR\u2010induced inflammatory arthritis"],"prefix":"10.1002","volume":"44","author":[{"given":"Nam\u2010Hoon","family":"Kim","sequence":"first","affiliation":[{"name":"POSTECH\u2010CATHOLIC BioMedical Engineering Institute The Catholic University of Korea  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Choi","sequence":"additional","affiliation":[{"name":"POSTECH\u2010CATHOLIC BioMedical Engineering Institute The Catholic University of Korea  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun\u2010Jin","family":"Han","sequence":"additional","affiliation":[{"name":"POSTECH\u2010CATHOLIC BioMedical Engineering Institute The Catholic University of Korea  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bong\u2010Ki","family":"Hong","sequence":"additional","affiliation":[{"name":"POSTECH\u2010CATHOLIC BioMedical Engineering Institute The Catholic University of Korea  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo Youn","family":"Choi","sequence":"additional","affiliation":[{"name":"School of Nano\u2010Bioscience and Chemical Engineering Ulsan National Institute of Science and Technology  Ulsan Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Moo","family":"Kwon","sequence":"additional","affiliation":[{"name":"School of Nano\u2010Bioscience and Chemical Engineering Ulsan National Institute of Science and Technology  Ulsan Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue\u2010Yun","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Animal Biotechnology Graduate School of Biology and Information Technology, Hankyoung National University  Ansung Kyunggi\u2010Do Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chul\u2010Soo","family":"Cho","sequence":"additional","affiliation":[{"name":"POSTECH\u2010CATHOLIC BioMedical Engineering Institute The Catholic University of Korea  Seoul Korea"},{"name":"Division of Rheumatology, Department of Internal Medicine Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan\u2010Uk","family":"Kim","sequence":"additional","affiliation":[{"name":"POSTECH\u2010CATHOLIC BioMedical Engineering Institute The Catholic University of Korea  Seoul Korea"},{"name":"Division of Rheumatology, Department of Internal Medicine Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,8,11]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(01)00165-0"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ibmb.2006.12.009"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.13.7214"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb816"},{"key":"e_1_2_7_6_1","first-page":"149","article-title":"A combinatorial role for NFAT5 in both myoblast migration and differentiation during skeletal muscle myogenesis. J. Cell","volume":"120","author":"O'Connor R. S.","year":"2007","journal-title":"Sci."},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.10.5477"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.30229"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111569"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2012.05.021"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-009-0051-z"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar427"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.08-107888"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0708704105"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M208138200"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4402222"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1200"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M502430200"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00378.2005"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2006.01.013"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2009.234"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21254"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3060225"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0304127"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.12.6883-6890.2000"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2007.10.053"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.20445"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4906(03)00237-0"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1996.0262"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(80)90108-2"},{"key":"e_1_2_7_31_1","doi-asserted-by":"crossref","first-page":"2932","DOI":"10.1128\/iai.65.7.2932-2940.1997","article-title":"Induction of nitric oxide synthesis and xanthine oxidase and their roles in the antimicrobial mechanism against Salmonella typhimurium infection in mice","volume":"65","author":"Umezawa K.","year":"1997","journal-title":"Infect. Immun."},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2013.61"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.40.1177"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000056762.69302.46"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.22.2934"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000188210.72062.10"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.111.234559"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01535258"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(07)28014-0"},{"key":"e_1_2_7_40_1","first-page":"3347","article-title":"Activation of p38 mitogen\u2010activated protein kinase is necessary for gemcitabine\u2010induced cytotoxicity in human pancreatic cancer cells","volume":"25","author":"Koizumi K.","year":"2005","journal-title":"Anticancer Res."},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.132"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(95)00700-J"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111783"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.24289"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.25017"}],"container-title":["European Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Feji.201343669","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/eji.201343669","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T08:30:41Z","timestamp":1696581041000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/eji.201343669"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,8,11]]},"references-count":44,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2014,9]]}},"alternative-id":["10.1002\/eji.201343669"],"URL":"https:\/\/doi.org\/10.1002\/eji.201343669","archive":["Portico"],"relation":{},"ISSN":["0014-2980","1521-4141"],"issn-type":[{"value":"0014-2980","type":"print"},{"value":"1521-4141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,8,11]]}}}