Enhanced Cellular Polysulfides Negatively Regulate TLR4 Signaling and Mitigate Lethal Endotoxin Shock

Tianli Zhang, Katsuhiko Ono, Hiroyasu Tsutsuki, Hideshi Ihara, Waliul Islam, Takaaki Akaike, Tomohiro Sawa

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)


Cysteine persulfide and cysteine polysulfides are cysteine derivatives having sulfane sulfur atoms bound to cysteine thiol. Accumulating evidence has suggested that cysteine persulfides/polysulfides are abundant in prokaryotes and eukaryotes and play important roles in diverse biological processes such as antioxidant host defense and redox-dependent signal transduction. Here, we show that enhancement of cellular polysulfides by using polysulfide donors developed in this study resulted in marked inhibition of lipopolysaccharide (LPS)-initiated macrophage activation. Polysulfide donor treatment strongly suppressed LPS-induced pro-inflammatory responses in macrophages by inhibiting Toll-like receptor 4 (TLR4) signaling. Other TLR signaling stimulants—including zymosan A-TLR2 and poly(I:C)-TLR3—were also significantly suppressed by polysulfur donor treatment. Administration of polysulfide donors protected mice from lethal endotoxin shock. These data indicate that cellular polysulfides negatively regulate TLR4-mediated pro-inflammatory signaling and hence constitute a potential target for inflammatory disorders. Zhang et al. developed potent persulfide donors consisting of sulfane sulfur atoms stabilized by N-acetyl-L-cysteine (NAC polysulfides) via disulfide bonds at both sides. Strong anti-inflammatory activity of NAC polysulfides was demonstrated in cultured macrophage models and a mouse endotoxin shock model.

Original languageEnglish
Pages (from-to)686-698.e4
JournalCell chemical biology
Issue number5
Publication statusPublished - 2019 May 16


  • cysteine persulfide
  • endotoxin shock
  • inflammation
  • innate immunity
  • metabolomics
  • polysulfide
  • signal transduction
  • sulfane sulfur
  • sulfur donor
  • toll-like receptors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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