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

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Abstract
Prostaglandin J2 (PGJ2) and its metabolites Δ12-PGJ2 and 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) are naturally occurring derivatives of prostaglandin D2 that have been suggested to exert antiinflammatory effects in vivo. 15d-PGJ2 is a high-affinity ligand for the peroxisome proliferator-activated receptor γ (PPARγ) and has been demonstrated to inhibit the induction of inflammatory response genes, including inducible NO synthase and tumor necrosis factor α, in a PPARγ-dependent manner. We report here that 15d-PGJ2 potently inhibits NF-κB-dependent transcription by two additional PPARγ-independent mechanisms. Several lines of evidence suggest that 15d-PGJ2 directly inhibits NF-κB-dependent gene expression through covalent modifications of critical cysteine residues in IκB kinase and the DNA-binding domains of NF-κB subunits. These mechanisms act in combination to inhibit transactivation of the NF-κB target gene cyclooxygenase 2. Direct inhibition of NF-κB signaling by 15d-PGJ2 may contribute to negative regulation of prostaglandin biosynthesis and inflammation, suggesting additional approaches to the development of antiinflammatory drugs.