{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T23:03:09Z","timestamp":1785366189674,"version":"3.55.0"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T00:00:00Z","timestamp":1704672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,2,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Inter-\u03b1-trypsin inhibitor heavy chain 4 (ITIH4) is a major protein in serum and reported to be upregulated at the onset of rheumatoid arthritis (RA). Its citrullinated form, cit-ITIH4, is specifically found in the serum and synovial fluid of patients with RA. However, the detailed function of ITIH4 in arthritis remains unknown. The aim of this study was to clarify the role of ITIH4 and cit-ITIH4 using experimental arthritis models. ITIH4 and cit-ITIH4 expression was examined in steady-state mice and two different arthritis models, and their pathological effects were examined in Itih4-deficient mice. In na\u00efve C57BL\/6 (WT) mice, ITIH4 was expressed as mRNA in the liver and the lung and was expressed as protein in serum and hepatocytes. In K\/BxN serum transferred arthritis (K\/BxN-STA) and collagen-induced arthritis (CIA), ITIH4 and cit-ITIH4 in sera were increased before the onset of arthritis, and cit-ITIH4 was further increased at the peak of arthritis. In Itih4-deficient mice, citrullinated proteins in serum and joints, especially 120 kDa protein, were clearly diminished; however, there was no significant difference in arthritis severity between WT and itih\u2212\/\u2212 mice either in the K\/BxN-STA or CIA model. CIA mice also exhibited pulmonary lesions and itih4\u2212\/\u2212 mice tended to show enhanced inflammatory cell aggregation compared to WT mice. Neutrophils in the lungs of itih4\u2212\/\u2212 mice were significantly increased compared to WT mice. In summary, ITIH4 itself did not alter the severity of arthritis but may inhibit autoimmune inflammation via suppression of neutrophil recruitment.<\/jats:p>","DOI":"10.1093\/cei\/uxae001","type":"journal-article","created":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T17:39:40Z","timestamp":1704735580000},"page":"302-312","source":"Crossref","is-referenced-by-count":3,"title":["Role of inter-alpha-trypsin inhibitor heavy chain 4 and its citrullinated form in experimental arthritis murine models"],"prefix":"10.1093","volume":"215","author":[{"given":"Tamaki","family":"Iwai","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Institute of Medicine, University of Tsukuba , Tsukuba , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9105-5806","authenticated-orcid":false,"given":"Ayako","family":"Ohyama","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Institute of Medicine, University of Tsukuba , Tsukuba , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsumu","family":"Osada","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Institute of Medicine, University of Tsukuba , Tsukuba , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taihei","family":"Nishiyama","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Institute of Medicine, University of Tsukuba , Tsukuba , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaru","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Institute of Medicine, University of Tsukuba , Tsukuba , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruka","family":"Miki","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Institute of Medicine, University of Tsukuba , Tsukuba , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromitsu","family":"Asashima","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Institute of Medicine, University of Tsukuba , Tsukuba , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1708-4402","authenticated-orcid":false,"given":"Yuya","family":"Kondo","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Institute of Medicine, University of Tsukuba , Tsukuba , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9067-0961","authenticated-orcid":false,"given":"Hiroto","family":"Tsuboi","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Institute of Medicine, University of Tsukuba , Tsukuba , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiya","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Transborder Medical Research Center, University of Tsukuba , Tsukuba , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Transborder Medical Research Center, University of Tsukuba , Tsukuba , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihito","family":"Ishigami","sequence":"additional","affiliation":[{"name":"Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology , Itabashi-ku , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7995-9294","authenticated-orcid":false,"given":"Isao","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Institute of Medicine, University of Tsukuba , Tsukuba , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,1,8]]},"reference":[{"key":"2024021916280011200_CIT0001","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1002\/art.20018","article-title":"Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors","volume":"50","author":"Nielen","year":"2004","journal-title":"Arthritis Rheum"},{"key":"2024021916280011200_CIT0002","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/art.30081","article-title":"Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fc\u03b3 receptor","volume":"63","author":"Sokolove","year":"2011","journal-title":"Arthritis Rheum"},{"key":"2024021916280011200_CIT0003","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1172\/JCI25422","article-title":"Antibodies against citrullinated proteins enhance tissue injury in 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