4-Octyl-itaconate and dimethyl fumarate inhibit COX2 expression and prostaglandin production in macrophages

Prostaglandins (PGs) are important proinflammatory lipid mediators, the significance of which is highlighted by the widespread and efficacious use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of inflammation. 4-Octyl itaconate (4-OI), a derivative of the Krebs cycle-derived metabolite itaconate, has recently garnered much interest as an anti-inflammatory agent. Here we show that 4-OI limits PG production in macrophages stimulated with the Toll-like receptor 1/2 (TLR1/2) ligand Pam3CSK4. This decrease in PG secretion is due to a robust suppression of COX2 expression by 4-OI, with both mRNA and protein levels decreased. Dimethyl fumarate (DMF), a fumarate derivative used in the treatment of multiple sclerosis (MS), with properties similar to itaconate, replicated the phenotype observed with 4-OI. We also demonstrate that the decrease in COX2 expression and inhibition of downstream prostaglandin production occurs in an NRF2-independent manner. Our findings provide a new insight into the potential of 4-OI as an anti-inflammatory agent and also identifies a novel anti-inflammatory function of DMF.