Abstract
We investigated whether peroxisome proliferator-activated receptor gamma (PPARgamma) ligands (ciglitazone, troglitazone, and 15-deoxy-Delta(12,14) prostaglandin J(2)) inhibited cyclooxygenase-2 (COX-2) induction in human epithelial cells. Ligands of PPARgamma 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 PPARgamma ligands. PMA-mediated induction of COX-2 promoter activity was inhibited by PPARgamma ligands; this suppressive effect was prevented by overexpressing a dominant negative form of PPARgamma 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 PPARgamma ligands. These findings raised questions about the mechanism underlying the anti-AP-1 effect of PPARgamma ligands. The induction of c-Jun by PMA was blocked by PPARgamma ligands. Overexpression of either c-Jun or CREB-binding protein/p300 partially relieved the suppressive effect of PPARgamma ligands. When CREB-binding protein and c-Jun were overexpressed together, the ability of PPARgamma ligands to suppress PMA-mediated induction of COX-2 promoter activity was essentially abrogated. Bisphenol A diglycidyl ether, a compound that binds to PPARgamma 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 PPARgamma ligands.
Highlights
We investigated whether peroxisome proliferator- tively expressed in most tissues and appears to be responsible activated receptor ␥ (PPAR␥) ligands
PPAR␥ Ligands Inhibit the Induction of COX-2 in Human Epithelial Cells—We determined the expression of PPAR␥ in human breast and oral epithelial cells
To investigate if the PPAR␥ receptor expressed in cell lines was transcriptionally active, 184B5/HER and MSK Leuk1 cells were transfected with a PPAR response element cloned upstream of luciferase (PPRE3-tk-luciferase)
Summary
We investigated whether peroxisome proliferator- tively expressed in most tissues and appears to be responsible activated receptor ␥ (PPAR␥) ligands PMA-mediated induction of COX-2 promoter activity was inhibited by PPAR␥ ligands; this suppressive effect was prevented by overexpressing a dominant negative form of PPAR␥ or a PPAR response element decoy oligonucleotide. When CREB-binding protein and c-Jun were overexpressed together, the ability of PPAR␥ ligands to suppress PMA-mediated induction of COX-2 promoter activity was essentially abrogated.
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