Inhibition of interleukin‐1β–induced cyclooxygenase 2 expression in human synovial fibroblasts by 15‐deoxy‐Δ<sup>12,14</sup>‐prostaglandin J<sub>2</sub> through a histone deacetylase–independent mechanism
Bibliographic record
Abstract
OBJECTIVE: The cyclooxygenase (COX) metabolite, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), has been reported to inhibit the expression of a number of genes involved in the pathogenesis of arthritis. However, its effects on COX-2 remain controversial. We undertook this study to investigate the effects of 15d-PGJ(2) on interleukin-1beta (IL-1beta)-induced COX-2 expression in human synovial fibroblasts (HSFs). METHODS: HSFs were cultured with IL-1beta in the absence or presence of 15d-PGJ(2), and the levels of COX-2 protein and messenger RNA (mRNA) expression were evaluated using Western blotting and real-time reverse transcriptase-polymerase chain reaction, respectively. COX-2 promoter activity was analyzed in transient transfection experiments. Chromatin immunoprecipitation assays were performed to evaluate the level of histone acetylation and the recruitment of histone deacetylases (HDACs) 1, 2, and 3 and histone acetylase (HAT) p300 to the COX-2 promoter. RESULTS: IL-1beta-induced COX-2 protein and mRNA expression, as well as COX-2 promoter activation, were inhibited by 15d-PGJ(2). Troglitazone, a selective peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, enhanced COX-2 expression, while GW9662, a specific PPARgamma antagonist, relieved the suppressive effect of 15d-PGJ(2). IL-1beta-induced histone H3 acetylation was selectively blocked by 15d-PGJ(2). The reduction of histone H3 acetylation did not correlate with the recruitment of HDACs to the COX-2 promoter. Also, treatment with the specific HDAC inhibitor, trichostatin A, did not relieve the suppressive effect of 15d-PGJ(2), indicating that HDACs are not involved in the inhibitory effect of 15d-PGJ(2). Furthermore, 15d-PGJ(2) blocked IL-1beta-induced recruitment of p300 to the COX-2 promoter, which may be the mechanism for decreased histone H3 acetylation and COX-2 expression. In accordance with this, overexpression of p300, but not of a mutant p300 lacking HAT activity, relieved the inhibitory effect of 15d-PGJ(2) on COX-2 promoter activation. CONCLUSION: These data suggest that 15d-PGJ(2) can inhibit IL-1beta-induced COX-2 expression by an HDAC-independent mechanism, probably by interfering with HAT p300.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".