title: IL-1β and TLR4 signaling are involved in the aggravated murine acute graft-versus-host disease caused by delayed bortezomib administration.
abstract: It was shown that the proteasome inhibitor, bortezomib, administered immediately following allogeneic bone marrow transplantation resulted in marked inhibition of acute graft-versus-host disease (aGVHD), with retention of graft-versus-tumor effects. However, continuous bortezomib administration resulted in significant acceleration of graft-versus-host disease-dependent morbidity. We carried out studies to dissect the mechanisms of aggravated aGVHD caused by delayed bortezomib administration. First, we demonstrated that IL-1β was critically involved, and the subsequent aGVHD could be alleviated by IL-1β blockade. Bortezomib treatment after dendritic cell (DC) activation resulted in drastically elevated IL-1β production, whereas bortezomib treatment before DC activation inhibited IL-1β production, suggesting that the timing of bortezomib administration significantly affected IL-1β 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-dependent 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-1β 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-1β.
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, People's Republic of China;
authors.forename: Yong
authors.initials: Y
authors.lastname: Liang
authors.forename: Shoubao
authors.initials: S
authors.lastname: Ma
authors.forename: Yanming
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Qiao
authors.initials: Q
authors.lastname: Cheng
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Yue
authors.initials: Y
authors.lastname: Jin
authors.forename: Donghui
authors.initials: D
authors.lastname: Zheng
authors.forename: Depei
authors.initials: D
authors.lastname: Wu
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
mesh_terms: D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D000069286:Bortezomib; D017690:Cell Transplantation; D003520:Cyclophosphamide / Q000008:administration & dosage; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006086:Graft vs Host Disease / Q000139:chemically induced* / Q000473:pathology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D015398:Signal Transduction / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000166:cytology; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D019172:Transplantation Conditioning / Q000379:methods; D014916:Whole-Body Irradiation
chemical_list: D001897:Boronic Acids; D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D011480:Protease Inhibitors; D011719:Pyrazines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000069286:Bortezomib; D003520:Cyclophosphamide