All-trans retinoic acid suppresses interleukin-6 expression in interleukin-1-stimulated synovial fibroblasts by inhibition of ERK1/2pathway independently of RAR activation
Bibliographic record
Abstract
INTRODUCTION: Interleukin-6 (IL-6) is thought to play a pathogenic role in rheumatoid arthritis and synovium is a major source of IL-6 release. We investigated the ability of retinoids to suppress IL-6 expression in IL-1-stimulated synovial fibroblasts, with special care to the contribution of retinoic acid receptor (RAR) and retinoid X receptor (RXR) subtypes, and the implication of the mitogen-activated protein kinase (MAPK) pathway. METHODS: RAR-alpha, -beta, and -gamma and RXR-alpha, -beta, and -gamma levels were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) or Western blot in rat synovial fibroblasts stimulated with 10 ng/mL of IL-1beta. Stimulated levels of IL-6 were assessed by RT-qPCR or immunoassays in the presence or absence of 1 microM all-trans retinoic acid (ATRA) (RAR agonist) or 0.3 microM BMS-649 (RXR agonist). The contribution of RAR subtypes was checked with selective agonists or small interfering RNAs. The effect of ATRA on upstream MAPK (p38 MAPK, c-Jun N-terminal kinase [JNK], and extracellularly regulated kinase 1/2 [ERK1/2]) was assessed by Western blot, and the contribution of the ERK1/2 pathway to the activation of pro-inflammatory transcription factors was studied by TransAm assays. RESULTS: Synovial fibroblasts expressed all RAR and RXR subtypes except RXR-gamma. In IL-1-stimulated cells, ATRA, but not BMS-649, reduced IL-6 expression whereas selective RAR agonists were inactive. The inhibitory effect of ATRA on IL-6 was not affected by the silencing of RAR subtypes. ATRA also reduced the phosphorylation of ERK1/2, but not of p38 MAPK or of JNK. The suppressive effect of ATRA on the activation of activator protein-1 (AP-1) and nuclear factor-IL-6 (NF-IL-6) was reproduced by the MEK1 (mitogen-activated protein extracellularly regulated kinase kinase 1) inhibitor PD-98059, whereas ATRA and PD-98059 had no effect on NF-kappaB activation. CONCLUSIONS: Among RAR and RXR agonists, only ATRA inhibited IL-1-induced IL-6 expression in rat synovial fibroblasts by inhibiting ERK1/2 pathway and subsequent activation of AP-1 and NF-IL-6 independently of RAR.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".