Fumarate Esters Are Distinguished by Differential Inhibition of the NF-κB Mediated Proinflammatory Response. (P1.205)
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".