Hydrogen sulfide suppresses oxidized low-density lipoprotein (ox-LDL)-stimulated monocyte chemoattractant protein 1 generation from macrophages via the nuclear factor κB (NF-κB) pathway

J Biol Chem. 2014 Apr 4;289(14):9741-53. doi: 10.1074/jbc.M113.517995. Epub 2014 Feb 18.


This study was designed to examine the role of hydrogen sulfide (H2S) in the generation of oxidized low-density lipoprotein (ox-LDL)-stimulated monocyte chemoattractant protein 1 (MCP-1) from macrophages and possible mechanisms. THP-1 cells and RAW macrophages were pretreated with sodium hydrosulfide (NaHS) and hexyl acrylate and then treated with ox-LDL. The results showed that ox-LDL treatment down-regulated the H2S/cystathionine-β-synthase pathway, with increased MCP-1 protein and mRNA expression in both THP-1 cells and RAW macrophages. Hexyl acrylate promoted ox-LDL-induced inflammation, whereas the H2S donor NaHS inhibited it. NaHS markedly suppressed NF-κB p65 phosphorylation, nuclear translocation, DNA binding activity, and recruitment to the MCP-1 promoter in ox-LDL-treated macrophages. Furthermore, NaHS decreased the ratio of free thiol groups in p65, whereas the thiol reductant DTT reversed the inhibiting effect of H2S on the p65 DNA binding activity. Most importantly, site-specific mutation of cysteine 38 to serine in p65 abolished the effect of H2S on the sulfhydration of NF-κB and ox-LDL-induced NF-κB activation. These results suggested that endogenous H2S inhibited ox-LDL-induced macrophage inflammation by suppressing NF-κB p65 phosphorylation, nuclear translocation, DNA binding activity, and recruitment to the MCP-1 promoter. The sulfhydration of free thiol group on cysteine 38 in p65 served as a molecular mechanism by which H2S inhibited NF-κB pathway activation in ox-LDL-induced macrophage inflammation.

Keywords: Hydrogen Sulfide; Inflammation; Macrophages; NF-κB; Sulfhydryl.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / genetics
  • Animals
  • Cell Line
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Cell Nucleus / pathology
  • Chemokine CCL2 / biosynthesis*
  • Chemokine CCL2 / genetics
  • Gasotransmitters / pharmacology*
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / genetics
  • Humans
  • Hydrogen Sulfide / pharmacology*
  • Inflammation / chemically induced
  • Lipoproteins, LDL / pharmacology
  • Lipoproteins, LDL / toxicity*
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mice
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*


  • CCL2 protein, human
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Gasotransmitters
  • Lipoproteins, LDL
  • RELA protein, human
  • RNA, Messenger
  • Rela protein, mouse
  • Transcription Factor RelA
  • oxidized low density lipoprotein
  • Hydrogen Sulfide