Peroxisome Proliferator-activated Receptor γ Ligands Suppress the Transcriptional Activation of Cyclooxygenase-2

Abstract

We investigated whether peroxisome proliferatoractivated receptor ␥ (PPAR␥) ligands (ciglitazone, troglitazone, and 15-deoxy-⌬ 12,14 prostaglandin J 2 ) inhibited cyclooxygenase-2 (COX-2) induction in human epithelial cells. Ligands of PPAR␥ 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␥ 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. 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␥ ligands. These findings raised questions about the mechanism underlying the anti-AP-1 effect of PPAR␥ ligands. The induction of c-Jun by PMA was blocked by PPAR␥ ligands. Overexpression of either c-Jun or CREB-binding protein/p300 partially relieved the suppressive effect of PPAR␥ ligands. 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. Bisphenol A diglycidyl ether, a compound that binds to PPAR␥ 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␥ ligands.

15-PGJ2, but not thiazolidinediones, inhibits cell growth, induces apoptosis, and causes downregulation of Stat3 in human oral SCCa cells

“…An association has been suggested between PPARg and COX-2, which has also been implicated in various human cancers, including head and neck SCCa (Chan et al, 1999;Dannenberg et al, 2001). PPARg activators may inhibit COX-2 expression, possibly through negative interference with NF-kB and/or AP-1 activation (Inoue et al, 2000;Subbaramaiah et al, 2001;Yang and Frucht, 2001). There is also evidence that supports the function of PPARg ligands as potent inhibitors of angiogenesis in vivo and in vitro, providing an additional mechanism that may partially account for the anticancer properties of PPARg (Bishop-Bailey and Hla, 1999;Xin et al, 1999).…”

Rapid induction of peroxisome proliferator–activated receptor γ expression in human monocytes by monosodium urate monohydrate crystals

“…PPAR␥ has recently been suggested to function as a negative regulator of inflammatory responses. PPAR␥ ligands are capable of reducing the expression of genes for cytokines (e.g., TNF␣, IL-6, and IL-1␤), iNOS, gelatinase B, scavenger receptor A, and COX-2 in activated macrophages (9,10,26).…”

Peroxisome Proliferator‐Activated Receptors: Potential Therapeutic Targets in Lung Disease?

“…Additionally, PPARs can inhibit transcriptional activity by binding to and sequestering proteins that act as coactivators of these transcription factors (e.g., CREB, a coactivator of AP-1). 44 Of note, not all proteins whose expression is regulated by these transcription factors may be inhibited in every cell type. For example, in mouse macrophages, rosiglitazone (RG), a PPARg ligand, inhibits some but not all proteins that are upregulated by lipopolysaccharide (LPS, endotoxin) or interferon-gamma (IFN-g).…”

“…26 In contrast, the PPARg ligands ciglitazone and rosiglitazone inhibit PMA-mediated increases in COX-2 protein in airway epithelial cells by inhibiting AP-1 signaling pathways. 44 PPARg liganddependent increases and decreases in COX-2 expression in smooth muscle and epithelial cells, respectively, may reflect cell type-specific effects or differences in liganddependent effects on basal vs. stimulus-mediated COX-2 expression.…”

“…12,24,44,[102][103][104][105][106] For example, in addition to modulating inflammation, there is growing evidence that NSAIDs (e.g., sulindac sulfide and indomethacin), as well as TZDs, may promote epithelial-cell differentiation by activating PPARg. 12,103 This was observed in vitro and in animal tumor models 107 for both nonsmall-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) lines.…”