{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:50:29Z","timestamp":1791316229831,"version":"4.3.1"},"reference-count":37,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2006,8,31]],"date-time":"2006-08-31T00:00:00Z","timestamp":1156982400000},"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":[[2006,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Activation of p38 MAPK is a key signaling step in chronic inflammation. Inhibition of p38 MAPK is considered to be a promising future strategy to control inflammatory diseases, but studies of compounds to inhibit this kinase have so far been limited to investigation of their side effects. We undertook the present study to investigate which specific molecule, among 4 different isoforms of p38 MAPK (\u03b1, \u03b2, \u03b3, and \u03b4), is predominantly expressed and activated in inflammation. Such knowledge could allow more specific targeting of p38 MAPK in inflammatory disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Studies were performed on inflamed tissue from patients with rheumatoid arthritis, as a prototype of inflammatory disease. The expression and activation of the \u03b1, \u03b2, \u03b3, and \u03b4 isoforms of p38 MAPK were examined by immunoblotting, immunoprecipitation, and immunohistochemistry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Immunoblot analysis revealed that \u03b1 and \u03b3 were the predominantly expressed p38 MAPK isoforms, whereas the other 2 isoforms were less frequently present. By immunohistochemistry, the expression of all p38 MAPK isoforms was localized to the synovial lining layer as well as to blood vessels. Colabeling with cell\u2010specific markers revealed that macrophages expressed the \u03b1 and \u03b3 isoforms, synovial fibroblasts the \u03b2 and \u03b3 isoforms, and granulocytes the \u03b4 isoform, whereas T lymphocytes were rarely positive for any p38 MAPK isoform. Double\u2010labeling with isoform\u2010specific antibody and pan\u2010p38 antibody against the phosphorylated form of p38 MAPK showed activation of the \u03b1 and \u03b3 isoforms. Occasional activation of the \u03b2 isoform was also noted in the synovial lining and the endothelium, whereas the \u03b4 isoform, although expressed in pericytes around blood vessels, was not phosphorylated. This phosphorylation pattern was confirmed in immunoprecipitation studies in which activated p38 MAPK from synovial tissue extracts was identified as p38 MAPK\u03b1 and \u2010\u03b3 but not p38 MAPK\u03b2 or \u2010\u03b4.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data show that the \u03b1 and \u03b3 isoforms of p38 MAPK dominate in chronic inflammation. Effective strategies to inhibit p38 MAPK should therefore aim to specifically target either or both of these isoforms.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.22080","type":"journal-article","created":{"date-parts":[[2006,8,31]],"date-time":"2006-08-31T17:27:57Z","timestamp":1157045277000},"page":"2745-2756","source":"Crossref","is-referenced-by-count":124,"title":["Differential tissue expression and activation of p38 MAPK \u03b1, \u03b2, \u03b3, and \u03b4 isoforms in rheumatoid arthritis"],"prefix":"10.1002","volume":"54","author":[{"given":"Adelheid","family":"Korb","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makiyeh","family":"Tohidast\u2010Akrad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erdal","family":"Cetin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Axmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef","family":"Smolen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Schett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,8,31]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-9629(96)00266-6"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072682"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/372739a0"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.30.17920"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.9.4355"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.2.295"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.48.30122"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.38.23668"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb00542.x"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200011)43:11<2501::AID-ANR18>3.0.CO;2-K"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1159\/000060522"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1109"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.21626"},{"key":"e_1_2_6_15_2","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/S0022-3565(24)35155-9","article-title":"RWJ 67657, a potent, orally active inhibitor of p38 mitogen\u2010activated protein kinase","volume":"291","author":"Wadsworth SA","year":"1999","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.20507"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1201380"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0898-6568(97)00042-9"},{"key":"e_1_2_6_19_2","doi-asserted-by":"crossref","first-page":"415","DOI":"10.4049\/jimmunol.162.1.415","article-title":"Evaluation of the role of mitogen\u2010activated protein kinases in the expression of inducible nitric oxide synthase by IFN\u2010\u03b3 and TNF\u2010\u03b1 in mouse macrophages","volume":"162","author":"Chan ED","year":"1999","journal-title":"J Immunol"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.5.2753"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1996.5886"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V93.3.857"},{"key":"e_1_2_6_23_2","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.4049\/jimmunol.160.4.1982","article-title":"p38 mitogen\u2010activated protein kinase activation is required for human neutrophil function triggered by TNF\u2010\u03b1 or FMLP stimulation","volume":"160","author":"Zu YL","year":"1998","journal-title":"J Immunol"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780310302"},{"key":"e_1_2_6_25_2","doi-asserted-by":"crossref","first-page":"4246","DOI":"10.4049\/jimmunol.162.7.4246","article-title":"Differential expression and activation of p38 mitogen\u2010activated protein kinase \u03b1, \u03b2, \u03b3, and \u03b4 in inflammatory cell lineages","volume":"162","author":"Hale KK","year":"1999","journal-title":"J Immunol"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1006\/prep.1998.0947"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.6.1301"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.3.1741"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.6849"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200012)43:12<2634::AID-ANR3>3.0.CO;2-1"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200107)44:7<1540::AID-ART277>3.0.CO;2-7"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.40.25029"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M204296200"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.4.2622"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.26.16415"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj20031628"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M302759200"},{"key":"e_1_2_6_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.23.10454-10464.2005"}],"container-title":["Arthritis &amp; Rheumatism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.22080","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.22080","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T18:44:19Z","timestamp":1736534659000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/art.22080"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,8,31]]},"references-count":37,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2006,9]]}},"alternative-id":["10.1002\/art.22080"],"URL":"https:\/\/doi.org\/10.1002\/art.22080","archive":["Portico"],"relation":{},"ISSN":["0004-3591","1529-0131"],"issn-type":[{"value":"0004-3591","type":"print"},{"value":"1529-0131","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,8,31]]}}}