A Novel Small-Molecule Inhibitor of Endosomal TLRs Reduces Inflammation and Alleviates Autoimmune Disease Symptoms in Murine Models
| Autor: | Suresh Panneerselvam, Sangdun Choi, Eunha Kim, Uisuk Jeong, Wook Kim, Hyeon-Jun Shin, Wook-Yong Baek, Eun Young Cho, June Sung, Gi-Young Kim, Asma Achek, Chang-Hee Suh, Mahesh Chandra Patra, Wang Hee Lee |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Anti-Inflammatory Agents
Quantitative Structure-Activity Relationship Inflammation Endosomes Article Small Molecule Libraries Mice Toll-like receptor medicine Animals Immunologic Factors Lupus Erythematosus Systemic Psoriasis autoimmune diseases Receptor lcsh:QH301-705.5 Autoimmune disease Binding Sites Chemistry Interleukin-6 Tumor Necrosis Factor-alpha QSAR Toll-Like Receptors NF-kappa B antagonist General Medicine TLR7 medicine.disease Mice Inbred C57BL Molecular Docking Simulation TAC5 RAW 264.7 Cells lcsh:Biology (General) TLR4 Cancer research Tumor necrosis factor alpha Female medicine.symptom Signal transduction endosomal TLR Protein Binding |
| Zdroj: | Cells, Vol 9, Iss 1648, p 1648 (2020) Cells Volume 9 Issue 7 |
| ISSN: | 2073-4409 |
| Popis: | Toll-like receptors (TLRs) play a fundamental role in the inflammatory response against invading pathogens. However, the dysregulation of TLR-signaling pathways is implicated in several autoimmune/inflammatory diseases. Here, we show that a novel small molecule TLR-inhibitor (TAC5) and its derivatives TAC5-a, TAC5-c, TAC5-d, and TAC5-e predominantly antagonized poly(I:C) (TLR3)-, imiquimod (TLR7)-, TL8-506 (TLR8)-, and CpG-oligodeoxynucleotide (TLR9)-induced signaling pathways. TAC5 and TAC5-a significantly hindered the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-&kappa B), reduced the phosphorylation of mitogen-activated protein kinases, and inhibited the secretion of tumor necrosis factor-&alpha (TNF-&alpha ) and interleukin-6. Besides, TAC5-a prevented the progression of psoriasis and systemic lupus erythematosus (SLE) in mice. Interestingly, TAC5 and TAC5-a did not affect Pam3CSK4 (TLR1/2)-, FSL-1 (TLR2/6)-, or lipopolysaccharide (TLR4)-induced TNF-&alpha secretion, indicating their specificity towards endosomal TLRs (TLR3/7/8/9). Collectively, our data suggest that the TAC5 series of compounds are potential candidates for treating autoimmune diseases such as psoriasis or SLE. |
| Databáze: | OpenAIRE |
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