1. Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation.
- Author
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McGuire VA, Ruiz-Zorrilla Diez T, Emmerich CH, Strickson S, Ritorto MS, Sutavani RV, Weiβ A, Houslay KF, Knebel A, Meakin PJ, Phair IR, Ashford ML, Trost M, and Arthur JS
- Subjects
- Animals, Cytokines genetics, MAP Kinase Signaling System genetics, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 3 genetics, Mitogen-Activated Protein Kinase 3 metabolism, NF-kappa B genetics, NF-kappa B metabolism, Polyubiquitin genetics, RAW 264.7 Cells, Toll-Like Receptors genetics, Cytokines metabolism, Dimethyl Fumarate pharmacology, MAP Kinase Signaling System drug effects, Polyubiquitin metabolism, Toll-Like Receptors metabolism
- Abstract
Dimethyl fumarate (DMF) possesses anti-inflammatory properties and is approved for the treatment of psoriasis and multiple sclerosis. While clinically effective, its molecular target has remained elusive - although it is known to activate anti-oxidant pathways. We find that DMF inhibits pro-inflammatory cytokine production in response to TLR agonists independently of the Nrf2-Keap1 anti-oxidant pathway. Instead we show that DMF can inhibit the E2 conjugating enzymes involved in K63 and M1 polyubiquitin chain formation both in vitro and in cells. The formation of K63 and M1 chains is required to link TLR activation to downstream signaling, and consistent with the block in K63 and/or M1 chain formation, DMF inhibits NFκB and ERK1/2 activation, resulting in a loss of pro-inflammatory cytokine production. Together these results reveal a new molecular target for DMF and show that a clinically approved drug inhibits M1 and K63 chain formation in TLR induced signaling complexes. Selective targeting of E2s may therefore be a viable strategy for autoimmunity.
- Published
- 2016
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