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 distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 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) | 0.000 | 0.000 |
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 teacher head, 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".