{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T20:46:37Z","timestamp":1775162797571,"version":"3.50.1"},"reference-count":28,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2011,1,28]],"date-time":"2011-01-28T00:00:00Z","timestamp":1296172800000},"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":[[2011,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Systemic lupus erythematosus (SLE) is a chronic inflammatory disease associated with aberrant immune cell function. Treatment involves the use of indiscriminate immunosuppression, which results in significant side effects. SLE T cells express high levels of calcium\/calmodulin\u2010dependent protein kinase type IV (CaMKIV), which translocates to the nucleus upon engagement of the T cell receptor\u2013CD3 complex and accounts for abnormal T cell function. The purpose of this study was to determine whether inhibition of CaMKIV would improve disease pathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We treated MRL\/<jats:italic>lpr<\/jats:italic> mice with KN\u201093, a CaMKIV inhibitor, starting at week 8 or week 12 of age and continuing through week 16 and evaluated skin lesions, proteinuria, kidney histopathology, proinflammatory cytokine production, and costimulatory molecule expression. We also determined the effect of silencing of <jats:italic>CAMK4<\/jats:italic> on interferon\u2010\u03b3 (IFN\u03b3) expression by human SLE T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CaMKIV inhibition in MRL\/<jats:italic>lpr<\/jats:italic> mice resulted in significant suppression of nephritis and skin disease, decreased expression of the costimulatory molecules CD86 and CD80 on B cells, and suppression of IFN\u03b3 and tumor necrosis factor \u03b1 production. In human SLE T cells, silencing of <jats:italic>CAMK4<\/jats:italic> resulted in suppression of IFN\u03b3 production.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We conclude that suppression of CaMKIV mitigates disease development in lupus\u2010prone mice by suppressing cytokine production and costimulatory molecule expression. Specific silencing of <jats:italic>CAMK4<\/jats:italic> in human T cells results in similar suppression of IFN\u03b3 production. Our data justify the development of small\u2010molecule CaMKIV inhibitors for the treatment of patients with SLE.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.30085","type":"journal-article","created":{"date-parts":[[2010,10,15]],"date-time":"2010-10-15T16:57:45Z","timestamp":1287161865000},"page":"523-529","source":"Crossref","is-referenced-by-count":92,"title":["Suppression of autoimmunity and organ pathology in lupus\u2010prone mice upon inhibition of calcium\/calmodulin\u2010dependent protein kinase type IV"],"prefix":"10.1002","volume":"63","author":[{"given":"Kunihiro","family":"Ichinose","sequence":"first","affiliation":[]},{"given":"Yuang\u2010Taung","family":"Juang","sequence":"additional","affiliation":[]},{"given":"Jos\u00e9 C.","family":"Crisp\u00edn","sequence":"additional","affiliation":[]},{"given":"Katalin","family":"Kis\u2010Toth","sequence":"additional","affiliation":[]},{"given":"George C.","family":"Tsokos","sequence":"additional","affiliation":[]}],"member":"311","published-online":{"date-parts":[[2011,1,28]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.771170"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2009.240"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2009.12.005"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI22854"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2005.00252.x"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-8411(92)90028-O"},{"key":"e_1_2_6_8_2","doi-asserted-by":"crossref","first-page":"2924","DOI":"10.4049\/jimmunol.157.7.2924","article-title":"B7 costimulation and autoantigen specificity enable B cells to activate autoreactive T cells","volume":"157","author":"Roth R","year":"1996","journal-title":"J Immunol"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.2007.02008.x"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0272-6386(03)00192-6"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2004060437"},{"key":"e_1_2_6_12_2","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.4049\/jimmunol.163.4.2322","article-title":"B7 costimulation in the development of lupus: autoimmunity arises either in the absence of B7.1\/B7.2 or in the presence of anti\u2010b7.1\/B7.2 blocking antibodies","volume":"163","author":"Liang B","year":"1999","journal-title":"J Immunol"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.6.3436"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.11.6046"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.7.5015"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070247"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1515"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-05-091173"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.6.4019"},{"key":"e_1_2_6_20_2","doi-asserted-by":"crossref","first-page":"2086","DOI":"10.1002\/art.27452","article-title":"Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus\u2010prone mice","volume":"62","author":"Deng GM","year":"2010","journal-title":"Arthritis Rheum"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.7.3915"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.22571"},{"key":"e_1_2_6_23_2","first-page":"365","article-title":"Primer3 on the WWW for general users and for biologist programmers","volume":"132","author":"Rozen S","year":"2000","journal-title":"Methods Mol Biol"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI750"},{"key":"e_1_2_6_25_2","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.4049\/jimmunol.159.5.2265","article-title":"The proliferative in vivo activities of lpr double\u2010negative T cells and the primary role of p59fyn in their activation and expansion","volume":"159","author":"Balomenos D","year":"1997","journal-title":"J Immunol"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/0167-5699(95)80019-0"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.12.8761"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1006\/clin.1997.4353"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7520604"}],"container-title":["Arthritis &amp; 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