Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto 860-8556, Japan.
Department of Biological Science, Graduate School of Science, Osaka Prefecture University, Osaka 599-8531, Japan.
Cell Chem Biol. 2019 May 16;26(5):686-698.e4. doi: 10.1016/j.chembiol.2019.02.003. Epub 2019 Mar 7.
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.
半胱氨酸过硫酸氢盐和半胱氨酸多硫化物是与半胱氨酸巯基结合的含硫烷硫原子的半胱氨酸衍生物。越来越多的证据表明，半胱氨酸过硫酸氢盐/多硫化物在原核生物和真核生物中含量丰富，在抗氧化宿主防御和氧化还原依赖的信号转导等多种生物过程中发挥重要作用。在这里，我们表明，使用本研究中开发的多硫化物供体增强细胞多硫化物会导致脂多糖（LPS）引发的巨噬细胞激活明显抑制。多硫化物供体处理通过抑制 Toll 样受体 4（TLR4）信号强烈抑制 LPS 诱导的巨噬细胞促炎反应。其他 TLR 信号刺激剂-包括酵母聚糖 A-TLR2 和多聚（I：C）-TLR3-也被多硫化物供体处理显著抑制。多硫化物供体的给药可保护小鼠免受致死性内毒素休克。这些数据表明，细胞内多硫化物负调节 TLR4 介导的促炎信号，因此构成炎症性疾病的潜在靶标。
