DMF, but not other fumarates, inhibits NF-κB activity in vitro in an Nrf2-independent manner

J Neuroimmunol. 2015 Jun 15;283:74-85. doi: 10.1016/j.jneuroim.2015.04.006. Epub 2015 Apr 23.

Abstract

Fumarate-containing pharmaceuticals are potent therapeutic agents that influence multiple cellular pathways. Despite proven clinical efficacy, there is a significant lack of data that directly defines the molecular mechanisms of action of related, yet distinct fumarate compounds. We systematically compared the impact of dimethyl fumarate (DMF), monomethyl fumarate (MMF) and a mixture of monoethyl fumarate salts (Ca(++), Mg(++), Zn(++); MEF) on defined cellular responses. We demonstrate that DMF inhibited NF-κB-driven cytokine production and nuclear translocation of p65 and p52 in an Nrf2-independent manner. Equivalent doses of MMF and MEF did not affect NF-κB signaling. These results highlight a key difference in the biological impact of related, yet distinct fumarate compounds.

Keywords: Cytokine; Dimethyl fumarate (DMF); Monoethyl fumarate (MEF); Monomethyl fumarate (MMF); Nuclear factor (erythroid-derived 2)-like 2 (Nrf2); Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB).

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Animals
  • Bone Neoplasms / pathology
  • Burkitt Lymphoma / pathology
  • Cations / pharmacology
  • Cell Line, Tumor
  • Cells, Cultured
  • Cytokines / metabolism
  • Dimethyl Fumarate
  • Fumarates / pharmacology*
  • Humans
  • In Vitro Techniques
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Maleates / pharmacology
  • Mice
  • Mice, Knockout
  • Molecular Structure
  • NF-E2-Related Factor 2 / deficiency
  • NF-E2-Related Factor 2 / physiology
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B p52 Subunit / metabolism
  • Neoplasm Proteins / antagonists & inhibitors
  • Osteosarcoma / pathology
  • Signal Transduction / drug effects
  • Spleen / cytology
  • Transcription Factor RelA / metabolism

Substances

  • Cations
  • Cytokines
  • Fumarates
  • Maleates
  • NF-E2-Related Factor 2
  • NF-kappa B
  • NF-kappa B p52 Subunit
  • Neoplasm Proteins
  • Nfe2l2 protein, mouse
  • RELA protein, human
  • Transcription Factor RelA
  • citraconic acid
  • Dimethyl Fumarate
  • ethyl fumarate