The effect of IL-1β inhibitor canakinumab (Ilaris®) on IL-6 production in human skeletal muscle cells
Bibliographic record
Abstract
Muscle inflammation is one of the hallmarks of Duchenne muscular dystrophy (DMD). Dystrophin-deficient skeletal muscle cells produce higher levels of pro-inflammatory cytokines such as interleukin 1β (IL-1β) in response to toll-like receptor stimulation compared to normal muscle skeletal cells. IL- 1β induces the human skeletal muscle secretion of the myokine Interleukin-6 (IL-6). Here, we evaluated the effect of a human IgG1κ monoclonal antibody (canakinumab (Ilaris®)) that specifically blocks the IL-1β effect on IL-6 secretion by human skeletal muscle cells. Canakinumab is an excellent candidate for therapeutic repositioning to treat DMD because it is an FDA-approved drug to treat periodic fever syndromes and systemic juvenile idiopathic arthritis. Unlike previous generations of IL-1 inhibitors, canakinumab is highly specific for the IL-1β ligand, has a longer half-life, and does not interfere with other IL-1-activated inflammatory pathways. Following cell culture optimization and viability assays to assess toxicity, skeletal muscle cells were stimulated with IL-1β (10 ng/mL) for 48 hours in the presence of nine concentrations of canakinumab ranging from 0.001 nM to 1000 nM, and IL-6 production was measured with an enzyme-linked immunosorbent assay. Pre-incubation of myoblasts with canakinumab before IL-1β-stimulation, significantly reduced IL-6 production at concentrations of 1, 10, 100, 250, and 1000 nM relative to controls, yielding an IC50 of 0.264 nM. On the other hand, co-incubation of canakinumab with IL-1β before addition to myoblasts resulted in a significant inhibition with the IC50 reducing to 0.126 nM, less than half of the previous method. Canakinumab also did not affect myotube viability at 10 nM and was also able to significantly reduce the production of IL-6, when the cells were stimulated with IL-1β (10 ng/ml). Taken together, our results show that canakinumab is a potent inhibitor of IL-1β signaling in muscle cells. These results align with previously published pre-clinical work with other IL-1 inhibitors in the mdx mouse model and support further investigation into the clinical utility of repositioning canakinumab to treat DMD.
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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".