PMID- 28272439 OWN - NLM STAT- MEDLINE DCOM- 20181106 LR - 20181113 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 7 DP - 2017 Mar 8 TI - Discovery of BVDU as a promising Drug for autoimmune diseases Therapy by Dendritic-cell-based functional screening. PG - 43820 LID - 10.1038/srep43820 [doi] LID - 43820 AB - 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-1beta 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. FAU - Chen, Shuai AU - Chen S AD - Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. FAU - Zhou, Jinfeng AU - Zhou J AD - Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. FAU - Cai, Yingying AU - Cai Y AD - Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. FAU - Zheng, Xinyuan AU - Zheng X AD - Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. FAU - Xie, Sirong AU - Xie S AD - Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. FAU - Liao, Yuhan AU - Liao Y AD - Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. FAU - Zhu, Yu AU - Zhu Y AD - Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. FAU - Qin, Chaoyan AU - Qin C AD - Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. FAU - Lai, Weiming AU - Lai W AD - Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. FAU - Yang, Cuixia AU - Yang C AD - Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. FAU - Xie, Xin AU - Xie X AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. AD - Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. FAU - Du, Changsheng AU - Du C AD - Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. AD - Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170308 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Interleukin-1beta) RN - 0 (Interleukin-6) RN - 187348-17-0 (Interleukin-12) RN - 2M3055079H (brivudine) RN - G34N38R2N1 (Bromodeoxyuridine) SB - IM MH - Animals MH - Autoimmune Diseases/*drug therapy/immunology MH - Bromodeoxyuridine/*analogs & derivatives/pharmacology MH - Cell Differentiation/*drug effects/immunology MH - Dendritic Cells/*drug effects/immunology/metabolism MH - Diabetes Mellitus, Experimental/drug therapy/immunology/pathology MH - Diabetes Mellitus, Type 1/drug therapy/immunology/pathology MH - Drug Discovery/methods MH - Encephalomyelitis, Autoimmune, Experimental/drug therapy/immunology/pathology MH - Humans MH - Interleukin-12/immunology/metabolism MH - Interleukin-1beta/immunology/metabolism MH - Interleukin-6/immunology/metabolism MH - Mice, Inbred C57BL PMC - PMC5341058 COIS- The authors declare no competing financial interests. EDAT- 2017/03/09 06:00 MHDA- 2018/11/07 06:00 PMCR- 2017/03/08 CRDT- 2017/03/09 06:00 PHST- 2016/08/25 00:00 [received] PHST- 2017/02/01 00:00 [accepted] PHST- 2017/03/09 06:00 [entrez] PHST- 2017/03/09 06:00 [pubmed] PHST- 2018/11/07 06:00 [medline] PHST- 2017/03/08 00:00 [pmc-release] AID - srep43820 [pii] AID - 10.1038/srep43820 [doi] PST - epublish SO - Sci Rep. 2017 Mar 8;7:43820. doi: 10.1038/srep43820.