Fumarate Inhibits TNF-α Release

Vertebrates utilize two forms of immunity to combat pathogens. Innate immunity is considered the first line of defense that utilizes immediate action and three barriers. Innate immunity responses typically occur within minutes of pathogen exposure resulting in cellular receptor activation and acute pro-inflammatory cytokine release. Inflammatory macrophages engage bacterial endotoxins, including Gram-negative lipopolysaccharide (LPS) and Gram-positive lipoteichoic acid (LTA). And respond by releasing tumor necrosis factor-α (TNF-α). While beneficial for neutralizing acute pathogen exposure, prolonged TNF-α release results in chronic inflammation and tissue damage. In the present study, we examined two methylated derivatives of a citric acid cycle intermediate, fumarate, as potential mediators of endotoxin-induced TNF-α release. We determined that 10µM dimethyl fumarate (DMF) significantly inhibited LPS-mediated soluble TNF-α released from the mouse monocyte cell line RAW 264.7, with no effect on cell viability or reactive oxygen species (ROS) generation. Monomethyl fumarate (MMF) and DMF showed minimal effects on cell viability or ROS generation. We found that DMF at 10µM is anti-inflammatory with minimal monocyte cytotoxicity. The cellular mechanism of DMF action remains unknown