RETRACTED: Peroxisome proliferator-activated receptor γ ligands suppress the transcriptional activation of cyclooxygenase-2 -: Evidence for involvement of activator protein-1 and CREB-binding protein/p300 (Retracted article. See vol. 295, pg. 291, 2020)

We investigated whether peroxisome proliferator-activated receptor gamma (PPAR gamma) ligands (ciglitazone, troglitazone, and 15-deoxy-Delta (12,14) prostaglandin J(2)) inhibited cyclooxygenase-2 (COX-2) induction in human epithelial cells. Ligands of PPAR gamma inhibited phorbol ester (phorbol 12-myristate 13-acetate, PMA)-mediated induction of COX-2 and prostaglandin E-2 synthesis. Nuclear run-offs revealed increased rates of COX-2 transcription after treatment with PMA, an effect that was inhibited by PPAR gamma ligands, PMA-mediated induction of COX-2 promoter activity was inhibited by PPAR gamma ligands; this suppressive effect was prevented by overexpressing a dominant negative form of PPAR gamma or a PPAR response element decoy oligonucleotide, The stimulatory effects of PMA were mediated by a cyclic AMP response element in the COX-2 promoter. Treatment with PMA increased activator protein-1 (AP-1) activity and the binding of c-Jun, c-Fos, and ATF-2 to the cyclic AMP response element, effects that were blocked by PPAR gamma ligands. These findings raised questions about the mechanism underlying the anti-AP-1 effect of PPAR gamma ligands. The induction of c-Jun by PMA was blocked by PPAR gamma ligands. Overexpression of either c-Jun or CREB-binding protein/p300 partially relieved the suppressive effect of PPAR gamma ligands. When CREB-binding protein and c-Jun were overexpressed together, the ability of PPAR gamma ligands to suppress PMA-mediated induction of COX-2 promoter activity was essentially abrogated. Bisphenol A diglycidyl ether, a compound that binds to PPAR gamma but lacks the ability to activate transcription, also inhibited PMA-mediated induction of AP-1 activity and COX-2. Taken together, these findings are likely to be important for understanding the anti-inflammatory and anti-cancer properties of PPAR gamma ligands.