Prostaglandin J 2 (PGJ 2 ) and its metabolites Δ 12 -PGJ 2 and 15-deoxy-Δ 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 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-PGJ 2 potently inhibits NF-κB-dependent transcription by two additional PPARγ-independent mechanisms. Several lines of evidence suggest that 15d-PGJ 2 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-PGJ 2 may contribute to negative regulation of prostaglandin biosynthesis and inflammation, suggesting additional approaches to the development of antiinflammatory drugs.