15-Deoxy-Δ(12,14)-prostaglandin J(2 )inhibits IL-1β-induced cyclooxygenase-2 expression in human synovial fibroblasts through a histone deacetylase-independent mechanism
Bibliographic record
Abstract
15-Deoxy-Δ -prostaglandin J 2 (15d-PGJ 2 ) is a natural ligand for peroxisome proliferator-activated receptor gamma (PPARγ) and has been reported to inhibit the expression of a number of inflammatory genes in several cell types. However, its effects on cyclooxygenase-2 (COX-2) expression remains controversial. In the present study, we investigated the effects of 15d-PGJ 2 on IL-1β-induced COX-2 expression in human synovial fibroblasts. COX-2 protein and mRNA expression were evaluated using western blotting and real-time PCR analysis, respectively. The 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 HDAC1, HDAC2, HDAC3, and p300 to the COX-2 promoter. 15d-PGJ 2 inhibited IL-1β-induced COX-2 protein and mRNA expression, as well as COX-2 gene promoter activation. The suppression of COX-2 protein expression was abrogated by the PPARγ antagonist, GW9662, suggesting that this effect is mediated by PPARγ. The induction of COX-2 by IL-1β is associated with hyperacetylation of histone H3 and H4 at the COX-2 promoter. Interestingly, 15d-PGJ 2 selectively blocked IL-1β-induced histone H3 acetylation. This reduction was demonstrated to not correlate with the recruitment of histone deacetylase (HDAC) 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 of15d-PGJ 2 on COX-2 expression. Furthermore, 15d-PGJ 2 blocked IL-1β-induced recruitment of the histone acetylase (HAT) p300 to the COX-2 promoter, which may be the mechanism for decreased histone H3 acetylation and COX-2 expression. In line with this, overexpression of p300, but not of a mutant p300 lacking HAT activity, relieved the inhibitory effect of 15d-PGJ2 on COX- 2 promoter activation. Our data suggest that 15d-PGJ 2 can inhibit IL-1β-induced COX-2 expression in a PPARγ-dependent, HDAC-independent mechanism, probably by interfering with the HAT p300.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.000 | 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 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".