title: DMF, but not other fumarates, inhibits NF-κB activity in vitro in an Nrf2-independent manner.
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.
authors.affiliation: Biogen, Inc., 115 Broadway, Cambridge, MA 02142, USA.
authors.forename: Geoffrey O
authors.initials: GO
authors.lastname: Gillard
authors.affiliation: Biogen, Inc., 115 Broadway, Cambridge, MA 02142, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Collette
authors.affiliation: Biogen, Inc., 115 Broadway, Cambridge, MA 02142, USA.
authors.forename: John
authors.initials: J
authors.lastname: Anderson
authors.affiliation: Biogen, Inc., 115 Broadway, Cambridge, MA 02142, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chao
authors.affiliation: Biogen, Inc., 115 Broadway, Cambridge, MA 02142, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Scannevin
authors.affiliation: Biogen, Inc., 115 Broadway, Cambridge, MA 02142, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Huss
authors.affiliation: Biogen, Inc., 115 Broadway, Cambridge, MA 02142, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Fontenot
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology; D002051:Burkitt Lymphoma / Q000473:pathology; D002412:Cations / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D000069462:Dimethyl Fumarate; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D012516:Osteosarcoma / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000166:cytology; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D002412:Cations; D016207:Cytokines; D005650:Fumarates; D008298:Maleates; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D009363:Neoplasm Proteins; C495636:Nfe2l2 protein, mouse; C498143:RELA protein, human; D051996:Transcription Factor RelA; C073341:citraconic acid; D000069462:Dimethyl Fumarate; C061175:ethyl fumarate
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)