Inhibition of interleukin-1beta-induced cyclooxygenase 2 expression in human synovial fibroblasts by 15-deoxy-Delta12,14-prostaglandin J2 through a histone deacetylase-independent mechanism.
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.[1]References
- Inhibition of interleukin-1beta-induced cyclooxygenase 2 expression in human synovial fibroblasts by 15-deoxy-Delta12,14-prostaglandin J2 through a histone deacetylase-independent mechanism. Farrajota, K., Cheng, S., Martel-Pelletier, J., Afif, H., Pelletier, J.P., Li, X., Ranger, P., Fahmi, H. Arthritis Rheum. (2005) [Pubmed]
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