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Tiamulin inhibits TNF-α and alleviates psoriasis-like dermatitis

  • Ruiyu Xiang
    Affiliations
    Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Genetic Skin Disease Center; Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
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  • Linghan Hu
    Affiliations
    Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Genetic Skin Disease Center; Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
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  • Siyuan Li
    Affiliations
    Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Genetic Skin Disease Center; Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
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  • Ziyu Wei
    Affiliations
    Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Genetic Skin Disease Center; Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
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  • Zhongya Song
    Affiliations
    Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Genetic Skin Disease Center; Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
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  • Zhiming Chen
    Affiliations
    Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Genetic Skin Disease Center; Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
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  • Yihe Liu
    Affiliations
    Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Genetic Skin Disease Center; Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
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  • Juan Liu
    Affiliations
    Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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  • Xiaoguang Lei
    Affiliations
    College of Chemistry and Molecular Engineering, Peking University, Beijing, China
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  • Yong Yang
    Correspondence
    Corresponding author.
    Affiliations
    Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Genetic Skin Disease Center; Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
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      Highlights

      • A high-throughput screening platform for small molecule TNF-α inhibitors was established based on two cell death models.
      • Through two rounds of screening in a library of 3256 compounds, TF was found as a novel TNF-α antagonist.
      • TF inhibited the expression of TNF-α-induced inflammatory factors and the up-regulation of NF-κB and MAPK pathways.
      • Systemic and topical administration of TF improved IMQ-induced psoriasis-like dermatitis in the mouse model.

      Abstract

      Background

      TNF-α elicits a cascade amplification effect in psoriasis. Macromolecule drugs targeting TNF-α are widely used for the clinical treatment of psoriasis. However, there are currently no effective small-molecule inhibitors that can be used in the clinic.

      Objective

      Novel TNF-α inhibitor was identified via high-throughput screening (HTS) and its anti-inflammatory activity was evaluated.

      Methods

      Two cell death models were established to identify inhibitors of TNF-α through HTS from a library of 3256 compounds. The effect of the inhibitor of TNF-α was tested by HaCaT cells in vitro and IMQ-induced psoriasis-like mouse model in vivo.

      Results

      Tiamulin fumarate (TF) was identified as an effective inhibitor of TNF-α. TF significantly blocked the NF-κB and MAPK signaling pathways in TNF-α-stimulated HaCaT cells. Additionally, systemic and topical administration of TF improved IMQ-induced psoriasis-like dermatitis in the mouse model.

      Conclusion

      Our study established a HTS method to identify TF as an inhibitor of TNF-α. The protective roles of TF in psoriasis-related inflammation reveal the potential therapeutic value of TF for psoriasis.

      Keywords

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