Folic acid inhibits homocysteine-induced superoxide anion production and nuclear factor kappa B activation in macrophages

Can J Physiol Pharmacol. 2006 Jan;84(1):141-7. doi: 10.1139/Y05-136.


Folic acid supplementation is a promising approach for patients with cardiovascular diseases associated with hyperhomocysteinemia. We have demonstrated that homocysteine (Hcy) activates nuclear factor-kappaB (NF-kappaB), a transcription factor that plays an important role in inflammatory responses. The aim of the present study was to investigate the effect of folic acid on Hcy-induced NF-kappaB activation in macrophages. Hcy treatment (100 micromol/L) resulted in NF-kappaB activation and increased monocyte chemoattractant protein-1 (MCP-1) expression in THP-1 derived macrophages. Hcy-induced NF-kappaB activation was associated with a significant increase in the intracellular superoxide anion levels. There was a significant increase in phosphorylation and membrane translocation of NADPH oxidase p47phox subunit in Hcy-treated cells. Addition of folic acid (200 ng/mL) to the culture medium abolished NADPH oxidase-dependent superoxide anion generation in macrophages by preventing phosphorylation of p47phox subunit. Consequently, Hcy-induced NF-kappaB activation and MCP-1 expression was inhibited. Such an inhibitory effect of folic acid was independent of its Hcy-lowering ability. Taken together, these results suggest that folic acid treatment can effectively inhibit Hcy-induced oxidative stress and inflammatory responses in macrophages. This may represent one of the mechanisms by which folic acid supplementation exerts a protective effect in cardiovascular disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism*
  • Folic Acid / pharmacology*
  • Gene Expression Regulation / drug effects
  • Homocysteine / pharmacology
  • Humans
  • Macrophages / metabolism*
  • NADPH Oxidases / metabolism
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • RNA, Messenger / metabolism
  • Superoxides / antagonists & inhibitors*
  • Superoxides / metabolism


  • Chemokine CCL2
  • NF-kappa B
  • RNA, Messenger
  • Homocysteine
  • Superoxides
  • Folic Acid
  • NADPH Oxidases
  • neutrophil cytosolic factor 1