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J Immunol. 2015 Oct 15;195(8):3912-21. doi: 10.4049/jimmunol.1500194. Epub 2015 Sep 14.

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7-9.

Author information

1
Immunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan;
2
Immunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan; Institute of Molecular Medicine, National Tsing-Hua University, Hsinchu 30013, Taiwan;
3
Immunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan; Department of Life Sciences, National Central University, Taoyuan 32001, Taiwan;
4
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli 35053, Taiwan;
5
Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan;
6
Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan;
7
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;
8
Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 10005, China;
9
School of Medicine, University of Nankai, Tianjin 300071, China;
10
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.

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.

PMID:
26371257
DOI:
10.4049/jimmunol.1500194
[Indexed for MEDLINE]
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