15-deoxy-Delta(12,14)-prostaglandin J(2) inhibits multiple steps in the NF-kappa B signaling pathway

Prostaglandin J(2)(PGJ(2)) and its metabolites Delta(12)-PGJ(2) and 15-deox y-Delta(12,14)-PGJ(2) (15d-PGJ(2)) are naturally occurring derivatives of p rostaglandin D-2 that have been suggested to exert antiinflammatory effects in vivo. 15d-PGJ(2) is a high-affinity ligand for the peroxisome prolifera tor-activated receptor gamma (pPAP gamma) and has been demonstrated to inhi bit the induction of inflammatory response genes, including inducible NO sy nthase and tumor necrosis factor alpha, in a PPAR gamma-dependent manner. W e report here that 15d-PGJ(2) potently inhibits NF-kappa B-dependent transc ription by two additional PPAR gamma-independent mechanisms. Several lines of evidence suggest that 15d-PGJ(2) directly inhibits NF-kappa B-dependent gene expression through covalent modifications of critical cysteine residue s in I kappa B kinase and the DNA-binding domains of NF-kappa B subunits. T hese mechanisms act in combination to inhibit transactivation of the NF-kap pa B target gene cyclooxygenase 2, Direct inhibition of NF-kappa B signalin g by 15d-PGJ(2) may contribute to negative regulation of prostaglandin bios ynthesis and inflammation, suggesting additional approaches to the developm ent of antiinflammatory drugs.