title: Discovery of BVDU as a promising Drug for autoimmune diseases Therapy by Dendritic-cell-based functional screening.
abstract: Dendritic cells (DCs) play a critical role in the pathogenesis of autoimmune diseases including multiple sclerosis, and targeting DCs' cytokines production is an important strategy for autoimmune diseases treatment. By establishing a high-throughput screening system, we analyzed LOPAC drug library to identify drugs that control the secretion of IL-6 by DCs, we selected the most likely candidate drug, BVDU, and found that it affected not only IL-6 production, but also that of IL-12, IL-1β during the DCs differentiation and maturation. The mechanism studies showed that BVDU treatment restricted the phosphorylation of MAP kinase, which played an important role in DC cytokine production. We further assessed the in vivo therapeutic potentials of BVDU on mouse models including EAE and STZ-induced T1D, and found that BVDU treated EAE mice exhibited significantly lower EAE clinical scores, decreased leukocyte infiltration in central nervous system lesions, and reduced demyelination. As in T1D mice, BVDU treatment also showed promising therapeutic effects based on both alleviated disease symptoms and tissue pathogenesis. More interestingly, the modulating effect of BVDU on IL-6 production was further verified in human primary DCs. The above data supported the promising application of our screen model, and also the potential of BVDU for autoimmune diseases therapy.
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Sirong
authors.initials: S
authors.lastname: Xie
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Chaoyan
authors.initials: C
authors.lastname: Qin
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Lai
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Cuixia
authors.initials: C
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.|Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Changsheng
authors.initials: C
authors.lastname: Du
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D055808:Drug Discovery / Q000379:methods; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D018664:Interleukin-12; C020235:brivudine; D001973:Bromodeoxyuridine