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However, continuous bortezomib administration resulted in significant acceleration of graft-versus-host disease\u2013dependent morbidity. We carried out studies to dissect the mechanisms of aggravated aGVHD caused by delayed bortezomib administration. First, we demonstrated that IL-1\u03b2 was critically involved, and the subsequent aGVHD could be alleviated by IL-1\u03b2 blockade. Bortezomib treatment after dendritic cell (DC) activation resulted in drastically elevated IL-1\u03b2 production, whereas bortezomib treatment before DC activation inhibited IL-1\u03b2 production, suggesting that the timing of bortezomib administration significantly affected IL-1\u03b2 production by DCs. We further demonstrated that delayed administration of bortezomib accelerated aGVHD through TLR4 signaling. Because the LPS levels were much lower with reduced-intensity conditioning compared with high-dose irradiation, the accelerated graft-versus-host disease\u2013dependent morbidity with delayed bortezomib administration could be rescued by reduced-intensity conditioning. Our studies suggested that TLR4 pathway activation and delayed bortezomib administration amplified the production of IL-1\u03b2 and other inflammatory cytokines, which resulted in accelerated aGVHD-dependent morbidity. These results indicated that decreased toxicity of continuous bortezomib administration could be achieved by reduced-intensity conditioning or by inhibiting IL-1\u03b2.<\/jats:p>","DOI":"10.4049\/jimmunol.1203428","type":"journal-article","created":{"date-parts":[[2013,12,21]],"date-time":"2013-12-21T06:33:42Z","timestamp":1387607622000},"page":"1277-1285","source":"Crossref","is-referenced-by-count":30,"title":["IL-1\u03b2 and TLR4 Signaling Are Involved in the Aggravated Murine Acute Graft-versus-Host Disease Caused by Delayed Bortezomib Administration"],"prefix":"10.1093","volume":"192","author":[{"given":"Yong","family":"Liang","sequence":"first","affiliation":[{"name":"Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University , Suzhou 215123,","place":["People\u2019s Republic of China"]},{"name":"Clinical Laboratory, Department of Hematology, The Affiliated Huai\u2019an Hospital of Xuzhou Medical College , Huai\u2019an 223002,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoubao","family":"Ma","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University , Suzhou 215123,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Clinical Laboratory, Department of Hematology, The Affiliated Huai\u2019an Hospital of Xuzhou Medical College , Huai\u2019an 223002,","place":["People\u2019s Republic of China"]},{"name":"Cyrus Tang Hematology Center, Department of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University , Suzhou 215006,","place":["People\u2019s Republic of 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215006,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiyan","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University , Suzhou 215123,","place":["People\u2019s Republic of China"]},{"name":"Cyrus Tang Hematology Center, Department of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University , Suzhou 215006,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2014,2,1]]},"reference":[{"key":"2025032404094990100_r1","doi-asserted-by":"crossref","first-page":"3268","DOI":"10.1182\/blood-2010-12-290403","article-title":"Effector CD4+ T cells, the cytokines they generate, and GVHD: something old and something 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