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Enhanced Cellular Polysulfides Negatively Regulate TLR4 Signaling and Mitigate Lethal Endotoxin Shock.
Tianli Zhang1, Katsuhiko Ono1, Hiroyasu Tsutsuki1
1Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto 860-8556, Japan.
Cell Chemical Biology
|March 12, 2019
Summary
Cellular polysulfides, abundant in cells, regulate inflammatory responses. Enhancing these compounds with novel donors inhibits Toll-like receptor 4 (TLR4) signaling, offering a new therapeutic target for inflammatory disorders.
Area of Science:
- Biochemistry
- Immunology
- Cell Biology
Background:
- Cysteine persulfides and polysulfides are cysteine derivatives containing sulfane sulfur.
- These compounds are abundant in various organisms and involved in biological processes like antioxidant defense and signal transduction.
Purpose of the Study:
- To investigate the role of cellular polysulfides in regulating inflammatory responses.
- To evaluate the therapeutic potential of enhancing cellular polysulfides for inflammatory disorders.
Main Methods:
- Development of novel polysulfide donors.
- Treatment of macrophages with polysulfide donors and lipopolysaccharide (LPS).
- Assessment of Toll-like receptor (TLR) signaling pathways and inflammatory cytokine production.
- In vivo studies using mouse models of endotoxin shock.
Main Results:
- Enhancement of cellular polysulfides inhibited LPS-initiated macrophage activation.
- Polysulfide donors suppressed LPS-induced Toll-like receptor 4 (TLR4) signaling and pro-inflammatory responses.
- Other TLR signaling pathways (TLR2, TLR3) were also inhibited by polysulfide donors.
- Administration of polysulfide donors protected mice against lethal endotoxin shock.
Conclusions:
- Cellular polysulfides negatively regulate TLR4-mediated pro-inflammatory signaling.
- Polysulfide donors represent a potential therapeutic strategy for inflammatory disorders.
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