期刊
TRANSLATIONAL PSYCHIATRY
卷 11, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41398-021-01266-1
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类别
资金
- NIH [R01-AA024095]
- Sage Therapeutics
- Bowles Center for Alcohol Studies at UNC School of Medicine
- NIAAA Resource funding [U24AA015512]
The research shows that 3 alpha, 5 alpha-THP inhibits the activation of TLR4, TLR2, and TLR7 signals, but not TLR3 signal, by blocking the TLR-MyD88 interaction. This inhibition leads to decreased production of pro-inflammatory mediators and supports the potential therapeutic use of 3 alpha, 5 alpha-THP for inflammatory diseases.
We have shown that endogenous neurosteroids, including pregnenolone and 3 alpha ,5 alpha -THP inhibit toll-like receptor 4 (TLR4) signal activation in mouse macrophages and the brain of alcohol-preferring (P) rat, which exhibits innate TLR4 signal activation. The current studies were designed to examine whether other activated TLR signals are similarly inhibited by 3 alpha ,5 alpha -THP. We report that 3 alpha ,5 alpha -THP inhibits selective agonist-mediated activation of TLR2 and TLR7, but not TLR3 signaling in the RAW246.7 macrophage cell line. The TLR4 and TLR7 signals are innately activated in the amygdala and NAc from P rat brains and inhibited by 3 alpha ,5 alpha -THP. The TLR2 and TLR3 signals are not activated in P rat brain and they are not affected by 3 alpha ,5 alpha -THP. Co-immunoprecipitation studies indicate that 3 alpha ,5 alpha -THP inhibits the binding of MyD88 with TLR4 or TLR7 in P rat brain, but the levels of TLR4 co-precipitating with TRIF are not altered by 3 alpha ,5 alpha -THP treatment. Collectively, the data indicate that 3 alpha ,5 alpha -THP inhibits MyD88- but not TRIF-dependent TLR signal activation and the production of pro-inflammatory mediators through its ability to block TLR-MyD88 binding. These results have applicability to many conditions involving pro-inflammatory TLR activation of cytokines, chemokines, and interferons and support the use of 3 alpha ,5 alpha -THP as a therapeutic for inflammatory disease.
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