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

Abstract

Prostaglandin J2 (PGJ2) and its metabolites ⌬ 12 -PGJ2 and 15-deoxy-⌬ 12,14 -PGJ2 (15d-PGJ2) are naturally occurring derivatives of prostaglandin D2 that have been suggested to exert antiinflammatory effects in vivo. 15d-PGJ 2 is a high-affinity ligand for the peroxisome proliferator-activated receptor ␥ (PPAR␥) and has been demonstrated to inhibit the induction of inflammatory response genes, including inducible NO synthase and tumor necrosis factor ␣, in a PPAR␥-dependent manner. We report here that 15d-PGJ2 potently inhibits NF-B-dependent transcription by two additional PPAR␥-independent mechanisms. Several lines of evidence suggest that 15d-PGJ2 directly inhibits NF-B-dependent gene expression through covalent modifications of critical cysteine residues in IB kinase and the DNA-binding domains of NF-B subunits. These mechanisms act in combination to inhibit transactivation of the NF-B target gene cyclooxygenase 2. Direct inhibition of NF-B signaling by 15d-PGJ 2 may contribute to negative regulation of prostaglandin biosynthesis and inflammation, suggesting additional approaches to the development of antiinflammatory drugs. P rostaglandin J 2 (PGJ 2 ) and its metabolites are naturally occurring derivatives of prostaglandin D 2 (PGD 2 ). The pathway for formation of these compounds involves sequential conversion of PGD 2 to PGJ 2 , ⌬ 12 -PGJ 2 , and 15-deoxy-⌬ 12,14 -PGJ 2 (15d-PGJ 2 ) (1). The last of these metabolites, 15d-PGJ 2 , is a high-affinity ligand for peroxisome proliferator-activated receptor ␥ (PPAR␥) (2, 3). 15d-PGJ 2 represses several genes in activated macrophages, including the inducible NO synthase (iNOS) and tumor necrosis factor ␣ (TNF␣) genes, and this repression is at least partly dependent on PPAR␥ expression (4-6). 15d-PGJ 2 is present in vivo during the resolution phase of inflammation, suggesting that it may function as a feedback regulator of the inflammatory response (7).Previous studies evaluating PPAR␥-dependent inhibition of iNOS expression indicated that 15d-PGJ 2 was significantly more effective than synthetic PPAR␥ ligands, despite binding to PPAR␥ with lower affinity (4). PGJ 2 and its metabolites are characterized by the presence of a cyclopentenone ring system that contains an electrophilic carbon that can react covalently by means of the Michael addition reaction with nucleophiles such as the free sulfhydryls of glutathione and cysteine residues in cellular proteins (1,8,9). This reactive center is not present in the synthetic PPAR␥ ligands and has been proposed to account for some of the receptor-independent biological actions of PGJ 2 , its metabolites, and the related cyclopentenone prostaglandins PGA 2 and PGA 1 (8, 9).The transcription factor NF-B plays a key role in the activation of inflammatory response genes (10). In resting cells, NF-B is sequestered in the cytoplasm by association with an inhibitory protein IB. In response to signaling by inflammatory cytokines, IB kinase (IKK) is activated and phosphorylates IB on two serine residues. IB is then ubiquitinated...

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