Cyclosporin A and FK506 Inhibit IL-12p40 Production through the Calmodulin/Calmodulin-dependent Protein Kinase-activated PI3K in LPS-Stimulated Human Monocytic Cells (94.19)
Bibliographic record
Abstract
Abstract Cyclosporine-A (CyA) and FK506 are immunosuppressive agents that are widely used to treat inflammatory and autoimmune disorders because of their ability to suppress the production of Th1 cytokines including IL-12. Both CyA and FK506 are potent inhibitors of calcineurin in the calcium signalling pathway. However, the role of calcium signalling in the regulation of human IL-12p40 production remains unknown. Interestingly, calcium and phosphoinositide 3-kinase (PI3K) signalling pathways have been shown to negatively regulate LPS-induced murine IL-12p40 production. Contrary to these observations, we show here that LPS-induced IL-12p40 production in human monocytic cells is positively regulated by calcium activated calmodulin- (CaM) and CaM-dependent protein kinase-II (CaMK-II)-activated PI3K. Furthermore, LPS induced the production of IL-12p40 by NFκB and AP-1 transcription factors through the activation of upstream CaM/CaMK-II. LPS-induced IL-12p40 production is known to be regulated by the c-Jun-N-terminal kinase (JNK) pathway. Importantly, both CyA and FK506 downregulated LPS-induced IL-12p40 transcription by inhibiting CaM/CaMK-II-activated PI3K and their downstream transcription factors NFκB and AP-1 independent of the JNK pathway.
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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 | 0.002 | 0.000 |
| 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 | 0.001 |
| 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".