{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T18:11:34Z","timestamp":1761675094309},"reference-count":0,"publisher":"Rockefeller University Press","issue":"6","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1994,12,1]]},"abstract":"<jats:p>The pleiotropic cytokine interleukin 6 (IL-6) plays a role in the pathogenesis of various diseases, such as multiple myeloma, autoimmune and inflammatory diseases and osteoporosis. Therefore, specific inhibitors of IL-6 may have clinical applications. We previously succeeded in developing receptor antagonists of IL-6 that antagonized wild-type IL-6 activity on the human Epstein-Barr virus (EBV)-transformed B cell line CESS and the human hepatoma cell line HepG2. However, these proteins still had agonistic activity on the human myeloma cell line XG-1. We here report the construction of a novel mutant protein of IL-6 in which two different mutations are combined that individually disrupt the association of the IL-6\/IL-6 receptor (R) alpha complex with the signaltransducing \"beta\" chain, gp130, but leave the binding of IL-6 to IL-6R alpha intact. The resulting mutant protein (with substitutions of residues Gln160 to Glu, Thr163 to Pro, and replacement of human residues Lys42-Ala57 with the corresponding residues of mouse IL-6) was inactive on XG-1 cells and weakly antagonized wild-type IL-6 activity on these cells. By introducing two additional substitutions (Phe171Leu, Ser177Arg), the affinity of the mutant protein for IL-6R alpha was increased fivefold, rendering it capable of completely inhibiting wild-type IL-6 activity on XG-1 cells. Moreover, this mutant also antagonized the activity of IL-6, but not that of leukemia inhibitory factor, oncostatin M, or GM-CSF on the human erythroleukemia cell line TF-1, demonstrating its specificity for IL-6. These data demonstrate the feasibility of developing specific IL-6R antagonists. The availability of such antagonists may offer an approach to specifically inhibit IL-6 activity in vivo.<\/jats:p>","DOI":"10.1084\/jem.180.6.2395","type":"journal-article","created":{"date-parts":[[2004,6,24]],"date-time":"2004-06-24T07:56:10Z","timestamp":1088063770000},"page":"2395-2400","update-policy":"http:\/\/dx.doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":47,"title":["Development of an interleukin (IL) 6 receptor antagonist that inhibits IL-6-dependent growth of human myeloma cells."],"prefix":"10.1084","volume":"180","author":[{"given":"F D","family":"de Hon","sequence":"first","affiliation":[{"name":"Department of Autoimmune Diseases, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Ehlers","sequence":"additional","affiliation":[{"name":"Department of Autoimmune Diseases, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Rose-John","sequence":"additional","affiliation":[{"name":"Department of Autoimmune Diseases, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S B","family":"Ebeling","sequence":"additional","affiliation":[{"name":"Department of Autoimmune Diseases, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H K","family":"Bos","sequence":"additional","affiliation":[{"name":"Department of Autoimmune Diseases, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L A","family":"Aarden","sequence":"additional","affiliation":[{"name":"Department of Autoimmune Diseases, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J P","family":"Brakenhoff","sequence":"additional","affiliation":[{"name":"Department of Autoimmune Diseases, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[1994,12,1]]},"container-title":["The Journal of experimental medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/180\/6\/2395\/1676476\/2395.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/180\/6\/2395\/1676476\/2395.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T06:31:43Z","timestamp":1690266703000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/180\/6\/2395\/25703\/Development-of-an-interleukin-IL-6-receptor"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1994,12,1]]},"references-count":0,"journal-issue":{"issue":"6","published-print":{"date-parts":[[1994,12,1]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.180.6.2395","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[1994,12,1]]}}}