Fumarate Esters Are Distinguished by Differential Inhibition of the NF-κB Mediated Proinflammatory Response. (P1.205)

OBJECTIVE: To compare the effect of dimethyl fumarate (DMF), monomethyl fumarate (MMF) and monoethyl fumarate (MEF) salts on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway activation and subsequent inflammatory responses. BACKGROUND: Fumarate-containing compounds have shown significant efficacy in treating diseases with autoimmune pathology. Delayed-release DMF is an oral therapeutic approved in the U.S., Canada, and Australia for relapsing multiple sclerosis (MS). A formulation of fumaric acid esters that includes a combination of DMF and three MEF salts is licensed in Germany as an oral therapy for severe psoriasis. Preclinical studies demonstrate that DMF can promote cytoprotective and anti-inflammatory responses, both of which would be expected to ameliorate autoimmune pathology. The NF-κB pathway is a pivotal regulator of innate and adaptive immunity and its deregulation is implicated in the chronic inflammation of autoimmune diseases. Previous studies have implicated inhibition of NF-κΒ activation as a significant component of the therapeutic effect of DMF. In contrast, the effects of MEF salts on NF-κB pathway activity have not been described. DESIGN/METHODS: The effects of DMF, MMF and MEF salts on NF-κB pathway activity were evaluated using NF-κB reporter cell lines, primary immune cell populations ex vivo, and immune responses in vivo. RESULTS: Individual fumarate esters differentially impact p100 processing and NF-κB-dependent transcription in reporter cell lines. Consistent with these results, we observed differential effects of the individual fumarates on NF-κB activity and pro-inflammatory gene expression in primary murine splenocytes. In vivo assays further characterized non-redundant effects of DMF, MMF, and MEF on NF-κB signaling. CONCLUSIONS: DMF, MMF, and/or MEF salts exert differential effects on the NF-κB pathway and downstream pro-inflammatory responses. Study supported by: Biogen Idec Inc. Author disclosures: All authors are full-time employees of Biogen Idec, Inc. Disclosure: Dr. Gillard has received personal compensation for activities with Biogen Idec as an employee. Dr. Gillard holds stock and/or stock options in Biogen Idec. Dr. Huss has received personal compensation in an editorial capacity for Biogen Idec. Dr. Huss holds stock and/or stock options in Biogen Idec. Dr. Anderson has received personal compensation for activities with Biogen Idec as an employee. Dr. Anderson holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Anderson was involved as an investigator. Dr. Collette has received personal compensation for activities with Biogen Idec as an employee. Dr. Bertolotti-Ciarlet has received personal compensation for activities with Biogen Idec as an employee. Dr. Scannevin has received personal compensation for activities with Biogen Idec as an employee. Dr. Scannevin holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Scannevin was involved as an investigator. Dr. Fontenot has received personal compensation for activities with Biogen Idec as an employee. Dr. Fontenot holds stock and/or stock options in Biogen Idec.