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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Article info
Publication history
Published online: May 20, 2022
Accepted:
May 17,
2022
Received in revised form:
April 22,
2022
Received:
March 4,
2022
Identification
Copyright
© 2022 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
