title: Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7-9.
abstract: Activation of TLR7-9 has been linked to the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. Thus, therapeutic applications of antagonists of these TLRs for such disorders are being investigated. Bortezomib (Velcade) is a proteasome inhibitor known to suppress activation of these TLRs. To identify novel TLR7-9 inhibitors, we searched the Gene Expression Omnibus database for gene expression profiles of bortezomib-treated cells. These profiles were then used to screen the Connectivity Map database for chemical compounds with similar functions as bortezomib. A natural antibiotic, thiostrepton, was identified for study. Similar to bortezomib, thiostrepton effectively inhibits TLR7-9 activation in cell-based assays and in dendritic cells. In contrast to bortezomib, thiostrepton does not inhibit NF-κB activation induced by TNF-α, IL-1, and other TLRs, and it is less cytotoxic to dendritic cells. Thiostrepton inhibits TLR9 localization in endosomes for activation via two mechanisms, which distinguish it from currently used TLR7-9 inhibitors. One mechanism is similar to the proteasome inhibitory function of bortezomib, whereas the other is through inhibition of endosomal acidification. Accordingly, in different animal models, thiostrepton attenuated LL37- and imiquimod-induced psoriasis-like inflammation. These results indicated that thiostrepton is a novel TLR7-9 inhibitor, and compared with bortezomib, its inhibitory effect is more specific to these TLRs, suggesting the potential therapeutic applications of thiostrepton on immunologic disorders elicited by inappropriate activation of TLR7-9.
authors.affiliation: Immunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan;
authors.forename: Chao-Yang
authors.initials: CY
authors.lastname: Lai
authors.affiliation: Immunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan; Institute of Molecular Medicine, National Tsing-Hua University, Hsinchu 30013, Taiwan;
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Yeh
authors.affiliation: Immunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan; Department of Life Sciences, National Central University, Taoyuan 32001, Taiwan;
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Lu
authors.affiliation: Immunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan;
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Liu
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli 35053, Taiwan;
authors.forename: Li-Rung
authors.initials: LR
authors.lastname: Huang
authors.affiliation: Immunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan;
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Kao
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan;
authors.forename: Huan-Yuan
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan;
authors.forename: Chi-Ying F
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Department of Dermatology, Kaohsiung Medical University Hospital, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Research Center for Applied Sciences, Academia Sinica, Taipei 11529, Taiwan;
authors.forename: Chung-Hsing
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 10005, China;
authors.forename: Yunping
authors.initials: Y
authors.lastname: Luo
authors.affiliation: School of Medicine, University of Nankai, Tianjin 300071, China;
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.affiliation: Immunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan; Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; and Research and Development Center for Immunology, China Medical University, Taichung 40402, Taiwan thchuang@nhri.org.tw.
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Chuang
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007375:Interleukin-1 / Q000276:immunology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D011565:Psoriasis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013883:Thiostrepton / Q000494:pharmacology*; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors* / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D007375:Interleukin-1; D008562:Membrane Glycoproteins; C495348:TLR7 protein, human; C495371:TLR9 protein, human; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D013883:Thiostrepton