Dimethyl fumarate (DMF) inhibits T-cell proliferation and induces apoptosis by depleting glutathione (GSH) and accumulating reactive oxygen species (ROS). Here, we show that DMF-induced oxidative stress disrupts multiple cell-signaling pathways, including MYC, leading to cell cycle arrest and impaired proliferative responses in activated T-cells.
ABSTRACT
Recent evidence indicates that the TCA cycle metabolite fumarate plays a specific role in modulating signaling pathways in immune cells. We have previously shown that dimethyl fumarate (DMF) reduces glutathione (GSH) activity and causes the accumulation of cellular reactive oxygen species (ROS), thereby compromising effector immune responses and metabolic activities in activated T-cells. However, the precise mechanism by which DMF modulates T-cell signaling pathways remains to be elucidated. This study demonstrates that DMF inhibits T-cell proliferation, independent of T-cell receptor (TCR) engagement, and this response is fully reversible by replenishing GSH. Immunoblot analysis showed that DMF had different impacts on TCR downstream signaling by decreasing MYC expression while promoting the phosphorylation of Akt and Erk1/2. Cell cycle analysis demonstrated that exposure to DMF led to negative regulation of cell cycle-related proteins and induced T-cells into G0/G1 arrest, which was also rescued by antioxidants. Several genes related to GSH synthesis were upregulated at the same time, suggesting that a potential compensatory response may occur to reduce oxidative burst following DMF treatment. Our results suggest that DMF-mediated oxidative stress alters a range of cell signaling pathways, including MYC, leading to cell cycle arrest and a defective proliferative response of T-cells during activation.