15-Deoxy-Δ 12,14 -prostaglandin J 2 inhibits multiple steps in the NF-κB signaling pathway

作者：Daniel S. Straus, Gabriel Pascual, Mei Li, John Sutton Welch, Mercedes Ricote, Chin-Hui Hsiang, Lei Lei Sengchanthalangsy, Gourisankar Ghosh, Christopher K. Glass · 发表于：Proceedings of the National Academy of Sciences · 年份：2000 · DOI：10.1073/pnas.97.9.4844 · 被引用次数：1010 · 研究领域：Peroxisome Proliferator-Activated Receptors、NF-κB Signaling Pathways、Inflammatory mediators and NSAID effects

Prostaglandin J(2) (PGJ(2)) and its metabolites Delta(12)-PGJ(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) are naturally occurring derivatives of prostaglandin D(2) that have been suggested to exert antiinflammatory effects in vivo. 15d-PGJ(2) is a high-affinity ligand for the peroxisome proliferator-activated receptor gamma (PPARgamma) and has been demonstrated to inhibit the induction of inflammatory response genes, including inducible NO synthase and tumor necrosis factor alpha, in a PPARgamma-dependent manner. We report here that 15d-PGJ(2) potently inhibits NF-kappaB-dependent transcription by two additional PPARgamma-independent mechanisms. Several lines of evidence suggest that 15d-PGJ(2) directly inhibits NF-kappaB-dependent gene expression through covalent modifications of critical cysteine residues in IkappaB kinase and the DNA-binding domains of NF-kappaB subunits. These mechanisms act in combination to inhibit transactivation of the NF-kappaB target gene cyclooxygenase 2. Direct inhibition of NF-kappaB signaling by 15d-PGJ(2) may contribute to negative regulation of prostaglandin biosynthesis and inflammation, suggesting additional approaches to the development of antiinflammatory drugs.