{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T14:37:31Z","timestamp":1771857451904,"version":"3.50.1"},"reference-count":29,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T00:00:00Z","timestamp":1646956800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20K16931"],"award-info":[{"award-number":["JP20K16931"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ACR Open Rheumatology"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Systemic juvenile idiopathic arthritis (sJIA) is characterized by fever, arthritis, rash, hepatosplenomegaly, and macrophage activation syndrome; however, its pathogenesis is still unclear. Elevated serum interleukin (IL)\u201018 concentrations and decreased natural killer (NK) cell activity are characteristic of active disease; thus, we examined IL\u201018 signaling in NK cells from sJIA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed mitogen\u2010activated protein kinase (MAPK) p38 and nuclear factor \u03ba light chain enhancer of activated B cells (NF\u03baB) p65 phosphorylation in NK cells after in vitro recombinant IL\u201018 (rIL\u201018) stimulation in 31 patients with sJIA. Associations between clinical features, serum IL\u201018, and phosphorylation intensity were analyzed. Furthermore, we investigated the effects of high IL\u201018 concentrations on phosphorylation in NK cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Patients were divided according to their disease activity: systemic features (n\u00a0=\u00a08), chronic arthritis (n\u00a0=\u00a07), remission on medication (n\u00a0=\u00a010), and remission off medication (n\u00a0=\u00a06). MAPK p38 and NF\u03baB p65 phosphorylation intensity were the highest in healthy controls, followed by remission off medication, remission on medication (vs. control; MAPK p38, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01; NF\u03baB p65, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05), chronic arthritis (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001), and systemic features (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001). The systemic features group showed a complete defect in phosphorylation. Serum IL\u201018 was the highest in the systemic features group followed by chronic arthritis, remission on medication (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01), remission off medication (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01), and healthy controls (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01). Phosphorylation intensity was negatively correlated with serum IL\u201018 (MAPK p38, <jats:italic>r<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.42; NF\u03baB p65, <jats:italic>r<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.54). Furthermore, healthy control NK cells were cultured with rIL\u201018; impaired phosphorylation was reproduced in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Impaired IL\u201018 signaling in NK cells correlated with disease activity in sJIA. High serum IL\u201018 exposure induces impaired MAPK and NF\u03baB phosphorylation in NK cells.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acr2.11426","type":"journal-article","created":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T08:44:15Z","timestamp":1646988255000},"page":"503-510","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Impaired Interleukin\u201018 Signaling in Natural Killer Cells From Patients With Systemic Juvenile Idiopathic Arthritis"],"prefix":"10.1002","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0898-0539","authenticated-orcid":false,"given":"Takashi","family":"Ohya","sequence":"first","affiliation":[{"name":"Yokohama City University  Yokohama Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenichi","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Yokohama City University  Yokohama Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayako","family":"Murase","sequence":"additional","affiliation":[{"name":"Yokohama City University  Yokohama Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4414-7720","authenticated-orcid":false,"given":"Seira","family":"Hattori","sequence":"additional","affiliation":[{"name":"Yokohama City University  Yokohama Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asami","family":"Ohara","sequence":"additional","affiliation":[{"name":"Yokohama City University, Yokohama, Kanagawa and Aichi Children's Health and Medical Center  Obu Aichi Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomo","family":"Nozawa","sequence":"additional","affiliation":[{"name":"Yokohama City University  Yokohama Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryoki","family":"Hara","sequence":"additional","affiliation":[{"name":"Yokohama City University and National Hospital Organization Yokohama Medical Center  Yokohama Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuichi","family":"Ito","sequence":"additional","affiliation":[{"name":"Yokohama City University  Yokohama Kanagawa 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