Subbaramaiah K, Lin D T, Hart J C, Dannenberg A J
Department of Medicine, Division of Gastroenterology, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, New York 10021, USA.
J Biol Chem. 2001 Apr 13;276(15):12440-8. doi: 10.1074/jbc.M007237200. Epub 2001 Jan 23.
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.
我们研究了过氧化物酶体增殖物激活受体γ（PPARγ）配体（曲格列酮、罗格列酮和15-脱氧-Δ12,14-前列腺素J2）是否能抑制人上皮细胞中环氧化酶-2（COX-2）的诱导。PPARγ配体抑制佛波酯（佛波醇12-肉豆蔻酸酯13-乙酸酯，PMA）介导的COX-2诱导和前列腺素E2合成。核转录分析显示，用PMA处理后COX-2转录速率增加，而这种效应被PPARγ配体抑制。PPARγ配体抑制PMA介导的COX-2启动子活性；通过过表达显性负性形式的PPARγ或PPAR反应元件诱饵寡核苷酸可阻止这种抑制作用。PMA的刺激作用由COX-2启动子中的环磷酸腺苷反应元件介导。用PMA处理可增加激活蛋白-1（AP-1）活性以及c-Jun、c-Fos和ATF-2与环磷酸腺苷反应元件的结合，而这些效应被PPARγ配体阻断。这些发现引发了关于PPARγ配体抗AP-1效应潜在机制的疑问。PMA诱导的c-Jun被PPARγ配体阻断。c-Jun或CREB结合蛋白/p300的过表达部分缓解了PPARγ配体的抑制作用。当CREB结合蛋白和c-Jun一起过表达时，PPARγ配体抑制PMA介导的COX-2启动子活性的能力基本被消除。双酚A二缩水甘油醚是一种能与PPARγ结合但缺乏激活转录能力的化合物，它也抑制PMA介导的AP-1活性诱导和COX-2。综上所述，这些发现可能对理解PPARγ配体的抗炎和抗癌特性很重要。
